Halaven: Indications, Dosage, Precautions, Adverse Effects
Россия
  • Россия
  • Украина

Halaven - Product Information

Manufacture: Eisai Inc.
Country: Canada
Condition: Breast Cancer, Breast Cancer, Metastatic, Liposarcoma, Metastatic Breast Cancer (Breast Cancer, Metastatic)
Class: Antineoplastics, Mitotic inhibitors
Form: Liquid solution, Intravenous (IV)
Ingredients: eribulin mesylate,ethanol, water

eribulin mesylate injection

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Non-medicinal
Ingredients
Intravenous Solution for injection:
0.5 mg/mL
None
For a complete listing see Dosage Forms, Composition and Packaging section.

Indications and Clinical Use

HALAVEN is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane administered in either the adjuvant or metastatic setting.

Geriatrics (>65 years of age)

No dose adjustments are recommended based on the age of the patient (see WARNINGS AND PRECAUTIONS – Geriatrics(>65 years of age)).

Pediatrics (<18 years of age)

The safety and effectiveness of HALAVEN in pediatric patients have not been established.

Contraindications

HALAVEN is contraindicated in patients with a history of hypersensitivity to HALAVEN or halichondrin B or its chemical derivatives.

Warnings and Precautions

Serious Warnings and Precautions

  • Neutropenia (see WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION)
  • QT/QTc interval prolongation (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests; DRUG INTERACTIONS; ACTION AND CLINICAL PHARMACOLOGY, Electrocardiography)
  • HALAVEN has not been studied in patients with severe hepatic impairment or End Stage Renal Disease (ESRD).

HALAVEN should be administered under the supervision of a physician experienced in the use of anti-cancer agents.

Carcinogenesis and Mutagenesis

Carcinogenicity studies were not conducted with eribulin mesylate.

Eribulin mesylate was positive in mammalian genotoxicity studies (see TOXICOLOGY – Genotoxicity).

Cardiovascular

HALAVEN is associated with QT/QTc interval prolongation (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests; DRUG INTERACTIONS; ACTION AND CLINICAL PHARMACOLOGY, Electrocardiography). Many drugs that cause QT/QTc prolongation are suspected to increase the risk of torsade de pointes. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death.

Use of HALAVEN in patients with congenital long QT/QTc syndrome should be avoided. The concomitant use of HALAVEN with another QT/QTc-prolonging drug should be avoided to the extent possible (see DRUG INTERACTIONS).

The safety of HALAVEN has not been established in patients with significant cardiovascular impairment (history of congestive heart failure New York Heart Association > Grade 2, unstable angina or myocardial infarction within the previous 6 months, or serious cardiac arrhythmia).

Hematologic

Myelosuppression is dose dependent and primarily manifested as neutropenia. Febrile neutropenia occurred in 5% of patients receiving HALAVEN. Fatal outcome has been observed due to complications with neutropenia.

Patients should have Absolute Neutrophil Count (ANC) values ≥1,500 cells/mm3 and platelets >100,000/mm3 at the initiation of treatment with HALAVEN. Frequent monitoring of complete blood counts should be performed on all patients receiving HALAVEN. Patients should only be retreated with HALAVEN when ANC is ≥1,000 cells/mm3, platelets are ≥75,000/mm3, and any other toxicity of a previous cycle has recovered to Grade ≤2 (except anemia) (see DOSAGE AND ADMINISTRATION).

Patients experiencing febrile neutropenia, severe neutropenia, or thrombocytopenia may require a subsequent reduction of the dose of HALAVEN.

Patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × the upper limit of normal (ULN) or bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia. Reduction of the starting dose for patients with ALT or AST >3 x ULN or bilirubin >1.5 x ULN should be considered. These patients should be monitored closely for toxicity.

Neurologic

Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in a pivotal study. Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered by the end of their follow-up period (median follow-up duration = 269 days, range 25–662 days).

Monitor patients closely for signs of peripheral neuropathy. Dosage in patients experiencing peripheral neuropathy should be adjusted according to the recommendations in Table 4 (see DOSAGE AND ADMINISTRATION).

HALAVEN may aggravate existing neuropathy and should be used with caution in patients with pre-existing neuropathy.

Special Populations

Pregnant Women

HALAVEN is a microtubule inhibitor, therefore, it is expected to cause fetal harm when administered to pregnant women. Embryo-fetal toxicity and teratogenicity occurred in pregnant rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area (see TOXICOLOGY section). There are no adequate and well-controlled studies with HALAVEN in pregnant women. Women should be advised not to become pregnant when taking HALAVEN, and should use effective contraception during and for at least 3 months after stopping treatment. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Nursing Women

It is not known whether HALAVEN is excreted into human milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions to HALAVEN in nursing infants, breast feeding must be avoided.

Pediatrics (<18 years of age)

The safety and effectiveness of HALAVEN in pediatric patients have not been established.

Geriatrics (>65 years of age)

Among the 827 patients who received the recommended dose of HALAVEN in the Phase 2/3 breast cancer studies, 121 patients (15%) were >65 -75 years of age and 17 patients (2%) were >75 years of age. The safety profile of HALAVEN in elderly patients (>65 years of age) was similar to that of patients ≤65 years of age. No dose adjustments are recommended based on the age of the patient.

Hepatic Impairment

Patients with mild or moderate hepatic impairment should receive a reduced dose. The recommended dose for patients with mild hepatic impairment (Child-Pugh A) is 1.1 mg/m2. The recommended dose for patients with moderate hepatic impairment (Child-Pugh) B) is 0.7 mg/m2. HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C); therefore, the use of HALAVEN is not recommended in these patients (see DOSAGE AND ADMINISTRATION, and ACTION AND CLINICAL PHARMACOLOGY – Special Populations and Conditions).

Renal Impairment

A study evaluated the pharmacokinetics of eribulin in patients with moderate (creatinine clearance (CrCl): 30 to 50 mL/min) or severe (CrCl: 15 to <30 mL/min) renal impairment. Compared to patients with normal renal function (CrCl: >80 mL/min), patients with moderate or severe renal impairment have 1.49-fold higher eribulin dose-normalized exposures. For patients with moderate or severe renal impairment (CrCl: 15 to 50 mL/min), a reduction of the dose to 1.1 mg/m2 is recommended. Caution and close monitoring of adverse reactions, particularly myelosuppression, is advised for patients with renal impairment. HALAVEN has not been studied in patients with End Stage Renal Disease (ESRD) (see DOSAGE AND ADMINISTRATION, Dosage Adjustment in Special Populations, and ACTION AND CLINICAL PHARMACOLOGY – Special Populations and Conditions).

Male Patients

Male patients with breast cancer have not been investigated in the pivotal clinical study. The effects of HALAVEN on human fertility are unknown. Testicular toxicity has been observed in rats and dogs (see TOXICOLOGY). Male patients should seek advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with HALAVEN.

Monitoring and Laboratory Tests

Complete blood count (CBC) evaluation and liver function tests should be performed prior to each dose. The frequency of CBC monitoring should be increased in patients who develop Grade 3 or 4 cytopenias.

Electrolyte Monitoring

HALAVEN has been associated with an increased incidence of hypokalemia. HALAVEN has also been associated with QT/QTc interval prolongation. Hypokalemia, hypocalcemia, and hypomagnesemia should be corrected prior to initiation of HALAVEN. Serum potassium, calcium, and magnesium should be monitored periodically during treatment.

ECG Monitoring

ECG monitoring is recommended in patients with risk factors for torsade de pointes, such as patients with cardiac disease (e.g., congestive heart failure, bradyarrhythmias), and patients on concomitant medications that prolong the QT interval, especially Class IA or III antiarrhythmics, (see WARNINGS AND PRECAUTIONS, Cardiovascular; DRUG INTERACTIONS; ACTION AND CLINICAL PHARMACOLOGY, Electrocardiography).

Adverse Reactions

Adverse Drug Reaction Overview

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%). Development of severe peripheral neuropathy occurred in 8% of patients (Table 1). The most common adverse reactions leading to a clinical intervention were neutropenia, nausea, constipation, pyrexia, peripheral neuropathy, arthralgia/myalgia, anemia, back pain, headache and leukopenia.

Adverse reactions leading to discontinuation (HALAVEN = 13%, Treatment of Physician’s Choice = 15%) or dose reductions (HALAVEN = 17%, Treatment of Physician’s Choice = 16%) were comparable between the treatment groups.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

In the pivotal randomized, controlled EMBRACE study (Study 305), 762 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). Of the randomized patients, 750 were treated. A total of 503 patients received HALAVEN and 247 patients in the control group received Treatment of Physician’s Choice (TPC). In the control group, 97% of patients received chemotherapy (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%) and 3% received hormonal therapy. The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy.

Table 1 reports the most common non-hematologic adverse reactions for HALAVEN and TPC occurring in at least 10% of patients in the EMBRACE Study.

Table 1. Non-hematologic Adverse Reactions with an Incidence of at Least 10% of Patients with Metastatic Breast Cancer (Safety Population) in the EMBRACE Study (Study 305)
MedDRA SOC and Preferred TermaHALAVEN
n=503
(%)
Treatment of Physician’s Choice
n=247
(%)
TotalGrade 3Grade ≥4TotalGrade 3Grade ≥ 4
Any Event993633933420
Gastrointestinal disorders
Nausea35102830
Constipation25102110
Diarrhea18001800
Vomiting181<11810
General disorders and administrative site conditions
Asthenia/Fatigueb549140111
Pyrexia21<1013<10
Mucosal inflammation9101020
Investigations
Weight decreased211NA14<1NA
Metabolism and nutrition disorders
Anorexia20101310
Musculoskeletal and connective tissue disorders
Arthralgia/Myalgia22<101210
Back pain161<171<1
Bone pain122<1920
Pain in extremity11101010
Nervous system disorders
Peripheral neuropathyc358<11620
Headache19<10120<1
Respiratory, thoracic, and mediastinal disorders
Dyspnead16411322
Cough140NA90NA
Skin and subcutaneous tissue disorders
Alopeciae45NANA10NANA
Palmar-plantar erythrodysesthesia syndrome1<101440

Abbreviations: CTCAE, NCI Common Terminology Criteria for Adverse Reactions (version 3.0); MedDRA, Medical Dictionary for Regulatory Activities; NA, not applicable (the CTCAE system does not have these grades for the reaction);

SOC, system organ class.

aPatients reporting >1 adverse reaction within a preferred term were counted only once for that preferred term. If an adverse reaction had >1 CTC grade, the highest CTC grade was used.

bAsthenia/Fatigue: HALAVEN=Grade4:1%; Grade5:0%; TPC=Grade4:<1%; Grade 5:<1%.

cThis term includes the preferred terms neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia.

dDyspnea: HALAVEN=Grade 4:0%; Grade 5:1%; TPC= Grade 4:1%; Grade 5:1%.

eAlopecia: HALAVEN=Grade 1:27%, Grade 2:18%; TPC= Grade 1:5%, Grade 2:4%.

Abnormal Hematologic and Clinical Chemistry Findings

Hematologic adverse reactions from the EMBRACE Study are reported in Table 2. Hematologic toxicities resulted in discontinuation in <1% of patients receiving HALAVEN. Febrile neutropenia occurred in 5% of patients receiving HALAVEN.

Table 2. Hematologic Adverse Reactions Among Patients with Metastatic Breast Cancer (Safety Population) in the EMBRACE Study (Study 305)
Hematology ParametersHALAVEN
(n=503)
Any Grade
%
Any Grade
%
Grade 3
%
Grade 4
%
Any Grade
%
Grade 3
%
Grade 4
%
Leukopenia8831564122
Neutropenia82292954149
Anemia782<17340
Lymphopenia721327192
Thrombocytopenia201<12912

The neutropenia observed was generally reversible and not cumulative; the mean time to nadir within a cycle was approximately 13 days and the mean time to recovery from severeneutropenia (<500 cells/mm3) to neutropenia ≤ Grade 2 (≥1000 cells/mm3) was approximately 8 days.

The frequent laboratory abnormalities from the EMBRACE Study are reported in Table 3.

Table 3.Laboratory Abnormalities Among Patients with Metastatic Breast Cancer (Safety Population) in the EMBRACE Study (Study 305)
Laboratory AbnormalitiesHALAVEN
(n=503)
Treatment of Physician’s Choice
(n=247)
Any GradeGrade 3
%
Grade 4
%
Any GradeGrade 3
%
Grade 4
%
Aspartate Aminotransferase735<16550
Alanine Aminotransferase61305020
Alkaline Phosphatase58506530
Albumin40104010
Hypokalemia38411521
Hypocalcemia35122513
Hypomagnesemia34202801
Hyponatremia32332552
Hypophosphatemia23611420
Hypercalcemia19<1212<11
Hyperkalemia18<111921
Hypermagnesemia174<11320
Total Bilirubin15102120
Creatinine14111310

The safety profile of HALAVEN in the other Phase 2 and Phase 3 studies was consistent with that observed in the randomized, active-controlled EMBRACE Study (Study 305).

Less Common Clinical Trial Adverse Drug Reactions (>3% to <10%)

Blood and Lymphatic System Disorders: Febrile neutropenia

Ear and Labyrinth Disorders: Vertigo

Eye Disorders: Lacrimation increased

Cardiac Disorders: Tachycardia

Gastrointestinal Disorders: Abdominal distension, abdominal pain, abdominal pain upper, dyspepsia, dry mouth, stomatitis

General Disorders and Administration Site Conditions: Edema peripheral, pain

Infections and Infestations: Nasopharyngitis, rhinitis, urinary tract infection, upper respiratory tract infection

Investigations: Alanine aminotransferase increased, aspartate aminotransferase increased, weight increased

Metabolism and Nutrition Disorders: Decreased appetite, hyperglycemia, hypokalemia, hypomagnesemia

Musculoskeletal and Connective Tissue Disorders: Muscle spasms, muscular weakness, musculoskeletal chest pain, musculoskeletal pain

Nervous System Disorders: Dizziness, dysgeusia, hypoesthesia, lethargy

Psychiatric Disorders: Anxiety, depression, insomnia

Respiratory, Thoracic, and Mediastinal Disorders: Pharyngolaryngeal pain

Skin and Subcutaneous Tissue Disorder: Pruritus, rash

Vascular Disorders: Hypertension

Other serious adverse reactions in the 1,222 patients treated with HALAVEN not included above, and for which there is a possibility of a causal relationship to HALAVEN, include sudden death, pneumonia, sepsis (including neutropenic sepsis), dehydration, renal failure, pulmonary embolism, and deep vein thrombosis.

Post-Market Adverse Drug Reactions

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.

Immune System Disorders Drug hypersensitivity

Hepatobiliary Disorders Hepatoxicity

Gastrointestinal Disorders Pancreatitis

Respiratory, Thoracic and Mediastinal disorders Interstitial lung disease

Drug Interactions

Other QT/QTc Prolonging Drugs

The concomitant use of Halaven with another QT/QTc-prolonging drug should be avoided to the extent possible. Drugs that have been associated with QT/QTc interval prolongation and/or torsade de pointes include, but are not limited to, the examples in the following list (Chemical/pharmacological classes are listed if some class members have been implicated in QT/QTc prolongation and/or torsade de pointes): Class IA antiarrhythmics, class III antiarrhythmics, class 1C antiarrhythmics; antipsychotics, antidepressants, opioids, macrolide antibiotics and analogues, quinolone antibiotics, antimalarials, azole antifungals, domperidone, 5-hydroxytryptamine (5-HT)3 receptor antagonists, tyrosine kinase inhibitors, histone deacetylase inhibitors, beta-2 adrenoceptor agonists.

Caution should be observed if HALAVEN is used with drugs that can disrupt electrolyte levels, including, but not limited to, the following: loop, thiazide, and related diuretics; laxatives and enemas; amphotericin B; high dose corticosteroids.

Current information sources should be consulted for approved drugs that prolong the QT/QTc interval or cause electrolyte disturbances.

Drug-Drug Interactions

Effects of CYP3A4 inhibitors and inducers on HALAVEN

A pharmacokinetic (PK) study demonstrated that eribulin exposure (area under the curve and maximal concentration) was similar when HALAVEN was administered in combination with ketoconazole, a potent inhibitor of cytochrome P450 3A4 (CYP3A4), compared to administration of HALAVEN alone. A population PK analysis showed no effect of CYP3A4 inhibitors or inducers on eribulin exposure. Therefore, no drug-drug interactions are expected with CYP3A4 inhibitors or inducers.

Effects of transport protein inhibitors on HALAVEN

Non-clinical studies indicated that eribulin is a P -gp substrate (see DETAILED PHARMACOLOGY -Pharmacokinetics). A PK study demonstrated that eribulin exposure was similar when administered in combination with ketoconazole, an inhibitor of P -gp, compared to administration of eribulin alone. Eribulin is weakly metabolized and is mainly eliminated, unchanged, in feces and to a lower extent in urine. The contribution of P-gp to the biliary and renal excretion of eribulin is unknown. The transport proteins involved in the excretion of eribulin have not been identified but inhibition of transport proteins could in theory give rise to increased exposure to eribulin. Caution should be exercised when HALAVEN is administered with inhibitors of transport proteins.

Effects of HALAVEN on Other Drugs

Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 or induce CYP1A2, CYP2C9, CYP2C19, or CYP3A4 enzymes at relevant clinical concentrations and is not expected to alter the plasma concentrations of other drugs that are substrates of these enzymes.

Drug-Lifestyle Interactions

No studies on the effects of HALAVEN on the ability to drive or use machines have been performed. HALAVEN may cause side effects such as tiredness (fatigue) and dizziness, which may lead to a minor or moderate influence on the ability to drive or use machines. Patients should be advised not to drive and/or use machinery if they feel tired or dizzy.

Dosage and Administration

Recommended Dose and Dosage Adjustment

General Dosing Information

The recommended dose of HALAVEN is 1.4 mg/m2 administered intravenously (IV) over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle.

Patients should have Absolute Neutrophil Count (ANC) values ≥1,500 cells/mm3 and platelets >100,000/mm3 at the initiation of treatment with HALAVEN.

Premedication with steroids and/or antihistamines to prevent hypersensitivity reactions is not required with the use of HALAVEN. No special tubing is required for the IV administration of

HALAVEN.

Dosage Adjustment During Treatment

Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.

Recommended dose delays

Do not administer HALAVEN on Day 1 or Day 8 for any of the following:

  • ANC < 1,000/mm3
  • Platelets < 75, 000/mm3
  • Grade 3 or 4 non-hematological toxicities

The Day 8 dose may be delayed for a maximum of 1 week

  • If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose.
  • If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate the next cycle no sooner than 2 weeks later.
Recommended dose reductions

If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a reduced dose as set out in Table 4.

Table 4. Dose Adjustment Recommendations
Event Description Recommended HALAVEN
Dose
Permanently reduce the 1.4 mg/m2 HALAVEN dose for any of the following:
ANC <500 cells/mm3 lasting >7 days
ANC <1,000 cells/mm3 with fever or infection
Platelets <25,000/mm3
Platelets <50,000/mm3 requiring transfusion
Non-hematologic Grade 3 or 4 toxicities
Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicity
1.1 mg/m2
Occurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m20.7 mg/m2
Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2Discontinue HALAVEN

ANC= absolute neutrophil count.

Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Reactions (CTCAE) version 3.0

Re-treatment criteria: Patients should only be re-treated with HALAVEN when absolute neutrophil count (ANC) is ≥1,000 cells/mm3, platelets are ≥75,000/mm3, and any other toxicity of a previous cycle has recovered to Grade ≤2 (except anemia).

Dosage Adjustment in Special Populations

Patients with Hepatic Impairment

The recommended dose for patients with mild hepatic impairment (Child-Pugh A) is 1.1 mg/m2 administered IV on Days 1 and 8 of a 21-day cycle. The recommended dose for patients with moderate hepatic impairment (Child Pugh B) is 0.7 mg/m2 administered IV on Days 1 and 8 of a 21-day cycle. HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C); therefore, the use of HALAVEN is not recommended in these patients.

>
Patients with Renal Impairment

The recommended dose for patients with moderate or severe renal impairment (CrCl: 15 to 50 mL/min) is 1.1 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. HALAVEN was not studied in patients with End Stage Renal Disease (ESRD); therefore the use of HALAVEN is not recommended in these patients.

Administration

HALAVEN is a sterile, ready-to-use, clear, colorless aqueous solution for IV administration. Each vial contains 1 mg of eribulin mesylate as a 0.5 mg/mL solution in ethanol:water (5:95).

HALAVEN solution should be aseptically withdrawn from the vial into a syringe and administered IV without dilution. Alternatively, HALAVEN may be diluted in up to 100 mL 0.9% sodium chloride. HALAVEN must not be mixed with other medicinal products.

HALAVEN should not be diluted or administered through an intravenous line containing solutions with dextrose.

HALAVEN is administered intravenously over 2 to 5 minutes.

No special tubing is required for the IV administration of HALAVEN.

Good peripheral venous access or a patent central line should be ensured before administration. There is no evidence that eribulin mesylate is a vesicant or an irritant. In the event of extravasation, treatment should be symptomatic.

Parenteral solution should be inspected visually for clarity, particulate matter, precipitation, discoloration, leakage etc. prior to administration. Only clear solution without particles, precipitate or discoloration or leakage should be used. Unused portion should be discarded.

Overdosage

One case of overdose of HALAVEN has been reported. The patient inadvertently received 8.6 mg of HALAVEN (approximately 4 times the planned dose) and subsequently developed a hypersensitivity reaction (Grade 3) on Day 3 and neutropenia (Grade 3) on Day 7. Both adverse reactions resolved with supportive care.

There is no known antidote for HALAVEN overdose. In the event of an overdose, the patient should be closely monitored. Management of overdose should include supportive medical interventions to treat the presenting clinical manifestations.

For management of a suspected drug overdose, consult the regional Poison Control Centre immediately.

Action and Clinical Pharmacology

Mechanism of Action

Eribulin is a non-taxane microtubule dynamics inhibitor belonging to the halichondrin class of antineoplastic agents. Eribulin inhibits the growth phase of microtubule dynamics without affecting the shortening phase and sequesters tubulin into nonproductive aggregates. Eribulin exerts its anticancer effects via a tubulin-based antimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged mitotic blockage.

Pharmacodynamics

Eribulin has in vivo antitumor activity in multiple human tumor xenografts in athymic nude mice.

Electrocardiography

The effect of HALAVEN on the electrocardiographic QT interval was assessed in an open-labelled, uncontrolled, multicentre, single-arm study in 26 patients with solid tumors who received treatment with 1.4 mg/m2 on Day 1 and Day 8 of a 21-day cycle. No effect on the QTc interval was observed on Day 1. On day 8 of treatment, QTc interval prolongation was evident. The largest mean increase from baseline was 10.5 msec (90% CI 4.9 to 16.2). The exposure to HALAVEN was similar on Day 1 and Day 8; therefore, differences in plasma concentration could not account for the delayed increase in the QTc interval.

Pharmacokinetics

The pharmacokinetics of eribulin is linear over the dose range of 0.25 mg/m2 to 4.0 mg/m2. Following 1.4 mg/m2 dose administration, the mean maximum plasma concentration (Cmax) ranged from 186 to 519 ng/mL and the mean exposure (AUC) ranged from 600 to 971 ng·hr/mL.

Distribution

The pharmacokinetics of eribulin is characterized by a rapid distribution phase followed by a prolonged elimination phase, with a mean terminal half-life of approximately 40 hours. It has a large volume of distribution (43 to 114 L/m2) and low clearance (1.16 to 2.42 L/hr/m2). Eribulin exposure after multiple dosing is comparable to that following a single dose. No significant accumulation of eribulin is observed on weekly administration.

The plasma protein binding of eribulin is low. At 100 to 1,000 ng/mL eribulin, the protein binding of eribulin ranges from 49% to 65% in human plasma.

Metabolism

Cytochrome P450 3A4 (CYP3A4) negligibly metabolizes eribulin in vitro. Eribulin inhibits CYP3A4 activity in human liver microsomes, but it is unlikely that eribulin will substantially increase the plasma levels of CYP3A4 substrates. Eribulin shows no induction potential for CYP1A, CYP2C9, CYP2C19, and CYP3A in primary human hepatocytes. No significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP2E1 was detected with eribulin concentrations up to 5 μM in pooled human liver microsomes. No significant inhibition of CYP3A4 was detected with eribulin concentrations up to 1µM (730 ng/mL) in pooled liver microsomes. Therefore, it is unlikely that eribulin will affect plasma levels of drugs that are substrates of CYP enzymes.

Unchanged eribulin was the major circulating species in plasma following administration of 14C-eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, confirming that there are no major human metabolites of eribulin.

Excretion

Eribulin is eliminated primarily in feces unchanged. After administration of 14C-eribulin to patients, approximately 82% of the dose was eliminated in feces and 9% in urine, indicating that renal clearance is not a significant route of eribulin elimination. Unchanged eribulin accounted for approximately 88% and 91% of the radioactive materials recovered in feces and urine respectively. Eribulin is a substrate of the drug efflux transporter P-gp in vitro.

Special Populations and Conditions

Effects of Age, Gender, and Race

Based on a population pharmacokinetic analysis, gender, race, and age do not have a significant effect on the pharmacokinetics of eribulin.

Effects of Hepatic Impairments

A Phase 1 study evaluated the pharmacokinetics of eribulin in patients with mild (Child-Pugh A, n=7) and moderate (Child-Pugh B, n=4) hepatic impairment. Compared to patients with normal hepatic function (n=6), exposure to eribulin increased 1.75-fold and 2.79-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m2 and 0.7 mg/m2 to patients with mild and moderate hepatic impairment respectively resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Dose reduction to 1.1 mg/m2 is recommended for patients with mild (Child-Pugh A) and to 0.7 mg/m2 for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C).

Effects of Renal Impairments

The pharmacokinetics of eribulin were evaluated in a Phase 1 study in patients with normal renal function (CrCl: > 80 mL/min), moderate (CrCl: 30 to 50 mL/min) or severe (CrCl: 15 to

<30 mL/min) renal impairment. Creatinine clearance estimates were calculated using the Cockcroft-Gault formula. Increase in dose-normalized Cmax was 1.31-fold (90% CI: 0.84-2.05) for moderate renal impairment and 2.02-fold (90% CI: 1.27-3.21) for severe renal impairment compared to normal renal function. Moderate and severe renal impairment increased mean dose-normalized AUC(0-inf) 1.49-fold (90% CI: 0.9-2.45) compared to normal renal function. Severity of renal impairment had no incremental effect on eribulin exposure. HALAVEN has not been studied in patients with End Stage Renal Disease (ESRD). The recommended dose for patients with moderate or severe renal impairment (CrCl: 15 to 50 mL/min) is 1.1 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle.

Storage and Stability

Store the vials in their original cartons. Store up to 25°C with excursions permitted to 30°C. Do not freeze.

Once withdrawn from the vial into a syringe, HALAVEN (0.5 mg/mL) may be stored for up to 6 hours at ambient temperature and lighting or up to 24 hours under refrigeration. Diluted solutions of HALAVEN (0.005 to 0.2 mg/mL in normal saline) may be stored for up to 48 hours refrigerated or for up to 24 hours at ambient temperature and lighting. Any unused portions of the vial should be discarded.

Diluted solutions of HALAVEN (0.005 to 0.2 mg/mL in normal saline) are compatible with IV bags for up to 48 hours, refrigerated or for up to 24 hours at ambient temperature and lighting.

Special Handling Instructions

Procedures for proper handling and disposal of anticancer drugs should be followed. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate (ASHP guidelines 2006, OSHA Manual (Section VI, Chapter 2) 1999, Polovich et al. 2005, and NIOSH Alert 2004).

Dosage Forms, Composition and Packaging

HALAVEN (eribulin mesylate injection) is a sterile, clear, colorless solution in a single use vial, one vial per carton, with a latex-free rubber stopper. The drug product contains 1.0 mg eribulin mesylate per vial in 2 mL of solution. The eribulin mesylate solution concentration is

0.5 mg/mL.

Inactive ingredients: dehydrated alcohol USP (5% v/v), hydrochloric acid (for pH adjustment), sodium hydroxide (for pH adjustment), water for injection USP (95% v/v).