Halaven
Generic
Name: eribulin mesylate
Dosage Form: injection
INDICATIONS AND USAGE
1.1 Metastatic Breast Cancer
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
in either the adjuvant or metastatic setting [see Clinical
Studies (14.1)].
1.2 Liposarcoma
Halaven is indicated for the
treatment of patients with unresectable or metastatic liposarcoma who have
received a prior anthracycline-containing regimen [see Clinical
Studies (14.2)].
DOSAGE AND
ADMINISTRATION
2.1 Recommended Dose
The recommended dose of
Halaven is 1.4 mg/m2administered intravenously over 2 to 5 minutes on
Days 1 and 8 of a 21-day cycle.
The recommended dose of
Halaven in patients with mild hepatic impairment (Child-Pugh A) is 1.1 mg/m2administered intravenously
over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in
Specific Populations (8.6)].
The recommended dose of
Halaven in patients with moderate hepatic impairment (Child-Pugh B) is 0.7 mg/m2administered intravenously
over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in
Specific Populations (8.6)].
The recommended dose of
Halaven in patients with moderate or severe renal impairment
(creatinine clearance (CLcr) 15-49 mL/min) is 1.1 mg/m2 administered
intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle [see Use in
Specific Populations (8.7)].
2.2 Dose Modification
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 1.
·
Do not re-escalate Halaven
dose after it has been reduced.
Table 1: Recommended Dose Reductions
|
|
Event Description
|
Recommended Halaven
Dose
|
|
Permanently reduce the 1.4 mg/m2 Halaven dose for any of
the
following:
|
1.1 mg/m2
|
|
ANC
<500/mm3 for >7 days
|
|
|
ANC
<1,000 /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
|
|
|
Occurrence of
any event requiring permanent dose reduction while receiving 1.1 mg/m2
|
0.7 mg/m2
|
|
Occurrence of
any event requiring permanent dose reduction while receiving 0.7 mg/m2
|
Discontinue Halaven
|
|
ANC = absolute neutrophil
count.
Toxicities graded in accordance with National Cancer Institute (NCI) Common
Terminology Criteria for Adverse Events
(CTCAE) version 3.0.
|
2.3 Instructions for Preparation and Administration
Aseptically withdraw the
required amount of Halaven from the single-use vial and administer undiluted or
diluted in 100 mL of 0.9% Sodium Chloride Injection, USP.
Do not
dilute in or administer through an intravenous line containing solutions with
dextrose. Do not administer in the same
intravenous line concurrent with the other medicinal products.
Store undiluted Halaven in the
syringe for up to 4 hours at room temperature or for up to 24 hours under
refrigeration (40°F or 4°C). Store diluted solutions of Halaven for up to
4 hours at room temperature or up to 24 hours under refrigeration.
Discard unused portions of the
vial.
DOSAGE FORMS AND
STRENGTHS
Injection: 1
mg/2 mL (0.5 mg/mL).
CONTRAINDICATIONS
None.
WARNINGS AND
PRECAUTIONS
5.1 Neutropenia
In Study 1, severe neutropenia
(ANC < 500/mm3) lasting more than one week occurred in 12% (62/503) of
patients with metastatic breast cancer, leading to discontinuation in <1% of
patients. Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4
neutropenia) occurred in 5% (23/503) of patients; two patients (0.4%) died from
complications of febrile neutropenia [see Adverse
Reactions (6.1)].
In Study 1, patients with
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3
× ULN (upper limit of normal) experienced a higher incidence of Grade 4
neutropenia and febrile neutropenia than patients with normal aminotransferase
levels. Patients with bilirubin > 1.5 × ULN also had a higher incidence
of Grade 4 neutropenia and febrile neutropenia.
In Study 2, severe neutropenia
(ANC < 500/mm3) lasting more than one week occurred in 12% (26/222) of
patients with liposarcoma or leiomyosarcoma. Febrile neutropenia occurred in
0.9% of patients treated with Halaven and fatal neutropenic sepsis in 0.9%
[see Adverse
Reactions (6.1)].
Monitor complete blood counts
prior to each dose; increase the frequency of monitoring in patients who
develop Grade 3 or 4 cytopenias. Delay administration of Halaven and reduce
subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia
lasting longer than 7 days [seeDosage
and Administration (2.2)]. Clinical studies of Halaven
did not include patients with baseline neutrophil counts below 1,500/mm3.
5.2 Peripheral Neuropathy
In Study 1, Grade 3 peripheral
neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of
patients with metastatic breast cancer (MBC). Peripheral neuropathy was the
most common toxicity leading to discontinuation of Halaven (5% of patients;
24/503) in Study
1. 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 within a median follow-up
duration of 269 days (range 25-662 days).
In Study 2, Grade 3 peripheral
neuropathy occurred in 3.1% (7/223) of Halaven-treated patients. Peripheral
neuropathy led to discontinuation of Halaven in 0.9% of patients. The median
time to first occurrence of peripheral neuropathy of any severity was 5 months
(range: 3.5 months to 9 months). Neuropathy lasting more than 60 days
occurred in 58% (38/65) of patients. Sixty three percent (41/65) had not
recovered within a median follow-up duration of 6.4 months (range: 27 days to
29 months).
Monitor patients closely for
signs of peripheral motor and sensory neuropathy. Withhold Halaven in patients
who experience Grade 3 or 4 peripheral neuropathy, until resolution to
Grade 2 or less [see Dosage
and Administration (2.2)].
5.3 Embryo-Fetal Toxicity
Based on findings from an
animal reproduction study and its mechanism of action, Halaven can cause fetal
harm when administered to a pregnant woman. There are no adequate and
well-controlled studies of Halaven in pregnant women. In animal reproduction
studies, eribulin mesylate caused embryo-fetal toxicity when administered to
pregnant rats during organogenesis at doses below the recommended human dose.
Advise pregnant women of the potential risk to a fetus. Advise females of
reproductive potential to use effective contraception during treatment with
Halaven and for at least 2 weeks following the final dose. Advise males
with female partners of reproductive potential to use effective contraception
during treatment with Halaven and for 3.5 months following the final dose [seeUse in
Specific Populations (8.1)].
5.4 QT Prolongation
In an uncontrolled open-label
ECG study in 26 patients, QT prolongation was observed on Day 8,
independent of eribulin concentration, with no QT prolongation observed on
Day 1. ECG monitoring is recommended if therapy is initiated in patients
with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT
interval, including Class Ia and III antiarrhythmics, and electrolyte
abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating
Halaven and monitor these electrolytes periodically during therapy. Avoid
Halaven in patients with congenital long QT syndrome.
ADVERSE REACTIONS
6.1 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 (5.1)]
·
Peripheral neuropathy [see Warnings
and Precautions (5.2)]
·
QT prolongation [see Warnings
and Precautions (5.4)]
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%).
Metastatic
Breast Cancer
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 [seeClinical
Studies (14.1)]. 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
|
|
Adverse Reactions
|
Halaven
n=503
|
Control Group
n=247
|
|
|
All Grades
|
≥ Grade 3
|
All Grades
|
≥ Grade 3
|
|
Blood and lymphatic system disordersb
|
|
Neutropenia
|
82%
|
57%
|
53%
|
23%
|
|
Anemia
|
58%
|
2%
|
55%
|
4%
|
|
Nervous system disorders
|
|
Peripheral
neuropathyc
|
35%
|
8%
|
16%
|
2%
|
|
Headache
|
19%
|
<1%
|
12%
|
<1%
|
|
General disorders
|
|
Asthenia/Fatigue
|
54%
|
10%
|
40%
|
11%
|
|
Pyrexia
|
21%
|
<1%
|
13%
|
<1%
|
|
Mucosal
inflammation
|
9%
|
1%
|
10%
|
2%
|
|
Gastrointestinal disorders
|
|
Nausea
|
35%
|
1%
|
28%
|
3%
|
|
Constipation
|
25%
|
1%
|
21%
|
1%
|
|
Vomiting
|
18%
|
1%
|
18%
|
1%
|
|
Diarrhea
|
18%
|
0
|
18%
|
0
|
|
Musculoskeletal and connective tissue disorders
|
|
Arthralgia/Myalgia
|
22%
|
<1%
|
12%
|
1%
|
|
Back
pain
|
16%
|
1%
|
7%
|
2%
|
|
Bone
pain
|
12%
|
2%
|
9%
|
2%
|
|
Pain
in extremity
|
11%
|
1%
|
10%
|
1%
|
|
Metabolism and nutrition disorders
|
|
Decreased
weight
|
21%
|
1%
|
14%
|
<1%
|
|
Anorexia
|
20%
|
1%
|
13%
|
1%
|
|
Respiratory, thoracic, and mediastinal disorders
|
|
Dyspnea
|
16%
|
4%
|
13%
|
4%
|
|
Cough
|
14%
|
0
|
9%
|
0
|
|
Skin and subcutaneous tissue disorders
|
|
Alopecia
|
45%
|
NAd
|
10%
|
NAd
|
|
Infections
|
|
Urinary
Tract Infection
|
10%
|
1%
|
5%
|
0
|
|
a adverse reactions were graded per National
Cancer Institute Criteria for Adverse Events version 4.0.
b based upon laboratory data.
c includes peripheral neuropathy,
peripheral sensorimotor neuropathy, peripheral motor neuropathy,
polyneuropathy, peripheral sensory neuropathy, and paraesthesia.
d not applicable; (grading system does not
specify > Grade 2 for alopecia).
|
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
Liposarcoma
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 (14.2)].
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
|
|
Adverse Reaction
|
Halaven
n=223
|
Dacarbazine
n=221
|
|
|
All Grades
|
Grades 3-4
|
All Grades
|
Grades 3-4
|
|
Nervous system disorders
|
|
Peripheral
Neuropathyc
|
29%
|
3.1%
|
8%
|
0.5%
|
|
Headache
|
18%
|
0%
|
10%
|
0%
|
|
General disorders
|
|
Pyrexia
|
28%
|
0.9%
|
14%
|
0.5%
|
|
Gastrointestinal disorders
|
|
Constipation
|
32%
|
0.9%
|
26%
|
0.5%
|
|
Abdominal paind
|
29%
|
1.8%
|
23%
|
4.1%
|
|
Stomatitis
|
14%
|
0.9%
|
5%
|
0.5%
|
|
Skin and subcutaneous tissue disorders
|
|
Alopecia
|
35%
|
NAe
|
2.7%
|
NAe
|
|
Infections
|
|
Urinary tract
infection
|
11%
|
2.2%
|
5%
|
0.5%
|
|
a Adverse reactions were graded per
National Cancer Institute Criteria for Adverse Events version 4.03 (NCI CTCAE
v4.03).
b Safety data from one study site
enrolling six patients were excluded.
c Includes peripheral neuropathy,
peripheral sensorimotor neuropathy, peripheral motor neuropathy,
polyneuropathy, peripheral sensory neuropathy, and paraesthesia.
d Includes abdominal pain, upper
abdominal pain, lower abdominal pain, abdominal discomfort.
e Not applicable; (grading system
does not specify > Grade 2 for alopecia).
|
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%
for All Grades or ≥2% for Grades 3 and 4)a (Study 2)†
|
|
Laboratory Abnormality
|
Halaven
|
Dacarbazine
|
|
|
All Grades
|
Grades 3 - 4
|
All Grades
|
Grades 3 – 4
|
|
Hematology
|
|
Anemia
|
70%
|
4.1%
|
52%
|
6%
|
|
Neutropenia
|
63%
|
32%
|
30%
|
8.9%
|
|
Chemistry
|
|
Increased
alanine aminotransferase (ALT)
|
43%
|
2.3%
|
28%
|
2.3%
|
|
Increased
aspartate aminotransferase (AST)
|
36%
|
0.9%
|
16%
|
0.5%
|
|
Hypokalemia
|
30%
|
5.4%
|
14%
|
2.8%
|
|
Hypocalcemia
|
28%
|
5%
|
18%
|
1.4%
|
|
Hypophosphatemia
|
20%
|
3.2%
|
11%
|
1.4%
|
|
a Each test incidence is based on the
number of patients who had both baseline and at least one on-study
measurement and at least 1 grade increase from baseline.Halaven group (range
221-222) and dacarbazine group (range 214-215)
† Laboratory results were graded per NCI
CTCAE v4.03.
|
6.2 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
DRUG INTERACTIONS
7.1 Effects of Other Drugs on Halaven
No drug-drug interactions are
expected with CYP3A4 inhibitors, CYP3A4 inducers or P-glycoprotein
(P-gp) inhibitors. Clinically meaningful differences in exposure (AUC) were not
observed in patients with advanced solid tumors when Halaven was administered
with or without ketoconazole (a strong inhibitor of CYP3A4 and a P-gp
inhibitor) and when Halaven was administered with or without rifampin (a CYP3A4
inducer) [see Clinical
Pharmacology (12.3)].
7.2 Effects of Halaven on Other Drugs
Eribulin does not inhibit
CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes or induce CYP1A2,
CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical concentrations. Eribulin
is not expected to alter the plasma concentrations of drugs that are substrates
of these enzymes [see Clinical
Pharmacology (12.3)].
USE IN SPECIFIC
POPULATIONS
8.1 Pregnancy
Risk Summary
Based on findings from an
animal reproduction study and its mechanism of action, Halaven can cause fetal
harm when administered to a pregnant woman [see Clinical
Pharmacology (12.1)]. There are no available data
on the use of Halaven during pregnancy. In an animal reproduction study,
eribulin mesylate caused embryo-fetal toxicity when administered to pregnant
rats during organogenesis at doses below the recommended human dose [see Data]. Advise pregnant women of the
potential risk to a fetus.
The estimated background risks
of major birth defects and miscarriage for the indicated populations are
unknown. In the U.S. general population, the estimated background risk of major
birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4%
and 15% to 20%, respectively.
Data
Animal
Data
In an embryo-fetal
developmental toxicity study, pregnant rats received intravenous infusion of
eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses
approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based
on body surface area. Increased abortion and severe fetal external or soft
tissue malformations, including the absence of a lower jaw and tongue, or
stomach and spleen, were observed at doses 0.64 times the recommended human
dose of 1.4 mg/m2based on body surface area. Increased embryo-fetal
death/resorption, reduced fetal weights, and minor skeletal anomalies
consistent with developmental delay were also reported at doses at or
above a maternally toxic dose of approximately 0.43 times the recommended
human dose.
8.2 Lactation
Risk Summary
There is no information
regarding the presence of eribulin mesylate or its metabolites in human milk,
the effects on the breastfed infant, or the effects on milk production. No
lactation studies in animals were conducted. Because of the
potential for serious adverse reactions in breastfed infants from eribulin
mesylate, advise women not to breastfeed during treatment with Halaven and
for 2 weeks after the final dose.
8.3 Females and Males of Reproductive Potential
Contraception
Females
Based on findings from an
animal reproduction study and its mechanism of action, Halaven can cause
fetal harm when administered to a pregnant woman [see Use in
Specific Populations (8.1)]. Advise females of
reproductive potential to use effective contraception during treatment with
Halaven and for at least 2 weeks following the final dose.
Males
Based on its mechanism of
action, advise males with female partners of reproductive potential to use
effective contraception during treatment
with Halaven and for 3.5 months following the final dose.
Infertility
Males
Based on animal data, Halaven
may result in damage to male reproductive tissues leading to impaired fertility
of unknown duration [see Nonclinical
Toxicology (13.1)].
8.4 Pediatric Use
The safety and effectiveness
of Halaven in pediatric patients below the age of 18 years have not been
established.
8.5 Geriatric Use
Study 1 did not include
sufficient numbers of subjects with metastatic breast cancer aged 65 years and
older to determine whether they respond differently from younger
subjects. Of the 827 subjects who received the recommended dose and
schedule of Halaven in clinical studies with advanced breast cancer, 15%
(121/827) were 65 and older, and 2% (17/827) patients were 75 and
older. No overall differences in safety were observed between these
subjects and younger subjects.
Clinical studies of Halaven
did not include a sufficient number of subjects in Study 2 aged 65 years
and older to determine whether they respond differently from younger subjects.
8.6 Hepatic Impairment
Administration of Halaven at a
dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with
moderate hepatic impairment resulted in similar exposure to eribulin as a dose
of 1.4 mg/m2 to patients with normal hepatic function. Therefore, a
lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment
(Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic
impairment (Child-Pugh B). Halaven was not studied in patients with severe
hepatic impairment (Child-Pugh C) [see Dosage and
Administration (2.1), Clinical
Pharmacology (12.3)].
8.7 Renal Impairment
For patients with moderate or
severe renal impairment (CLcr 15-49 mL/min), reduce the starting dose
to 1.1 mg/m2 [see Dosage
and Administration (2.1), Clinical
Pharmacology (12.3)].
OVERDOSAGE
Overdosage
of Halaven has been reported at approximately 4 times the recommended dose,
which resulted in Grade 3 neutropenia lasting seven days and a Grade 3
hypersensitivity reaction lasting one day.
There
is no known antidote for Halaven overdose.
DESCRIPTION
Halaven
contains eribulin mesylate, a microtubule dynamics inhibitor. Eribulin
mesylate is a synthetic analogue of halichondrin B, a product isolated from the
marine sponge Halichondria okadai. The chemical name for eribulin mesylate is
11,15:18,21:24,28-Triepoxy-7,9-ethano-12,15-methano-9H,15H-furo[3,2-i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one,
2-[(2S)-3-amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-,
(2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-,
methanesulfonate (salt). It has a molecular weight of 826.0 (729.9 for free
base). The empirical formula is C40H59NO11•CH4O3S.
Eribulin mesylate has the following structural formula:
Halaven is a clear, colorless,
sterile solution for intravenous administration. Each vial contains 1 mg of
eribulin mesylate as a 0.5 mg/mL solution in ethanol: water (5:95).
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Eribulin inhibits the growth
phase of microtubules without affecting the shortening phase and sequesters
tubulin into nonproductive aggregates. Eribulin exerts its 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.
In addition, eribulin
treatment of human breast cancer cells caused changes in morphology and
gene expression as well as decreased migration and invasiveness in vitro.
In mouse xenograft models of human breast cancer, eribulin treatment was
associated with increased vascular perfusion and permeability in the tumor
cores, resulting in reduced tumor hypoxia, and changes in the expression of
genes in tumor specimens associated with a change in phenotype.
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effect of Halaven on the
QTc interval was assessed in an open-label, uncontrolled, multicenter,
single-arm dedicated QT trial. A total of 26 patients with solid tumors
received 1.4 mg/m2 of Halaven on Days 1 and 8 of a 21-day cycle. A delayed
QTc prolongation was observed on Day 8, with no prolongation observed on Day 1.
The maximum mean QTcF change from baseline (95% upper confidence
interval) was 11.4 (19.5) ms.
12.3 Pharmacokinetics
The pharmacokinetics (PK)
of eribulin is linear with a mean elimination half-life of approximately 40
hours, a mean volume of distribution of 43 L/m2 to 114 L/m2 and mean clearance of
1.16 L/hr/m2 to 2.42 L/hr/m2 over the dose range of 0.25 mg/m2 to 4.0 mg/m2. The human plasma
protein binding of eribulin at concentrations of 100 ng/mL to 1,000 ng/mL
ranges from 49% to 65%. Eribulin exposure after multiple dosing is comparable
to that following a single dose. No accumulation of eribulin is observed with
weekly administration.
Elimination
Metabolism
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. Cytochrome
P450 3A4 (CYP3A4) negligibly metabolizes eribulin in
vitro.
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.
Unchanged eribulin accounted for approximately 88% and 91% of total eribulin in
feces and urine, respectively.
Specific
Populations
Age, Sex, and Race/Ethnicity: Based
on a population pharmacokinetic analysis with data collected from 340 patients,
sex, race, and age do not have a clinically meaningful effect on the exposure
of eribulin.
Hepatic
Impairment
In a study evaluating the
effect of hepatic impairment on the PK of eribulin, eribulin exposures
increased by 1.8-fold in patients with mild hepatic impairment (Child-Pugh A;
n=7) and by 2.5-fold in patients with moderate (Child-Pugh B; n=5) hepatic
impairment as compared to patients with normal hepatic function (n=6).
Administration of Halaven at a dose of 1.1 mg/m2 to patients with mild
hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in
similar exposure to eribulin at a dose of 1.4 mg/m2 to patients with normal
hepatic function [see Dosage
and Administration (2.1), Use in
Specific Populations (8.6)].
Renal
Impairment
In a study evaluating the
effect of renal impairment on the PK of eribulin, patients with moderate (CLcr
30-49 mL/min; n=7) and severe renal impairment (CLcr 15-29 mL/min; n=6) had
1.5-fold higher eribulin dose-normalized exposures compared to that in patients
with normal renal function (CLcr ≥ 80 mL/min; n=6). There were no
clinically meaningful changes in patients with mild renal impairment (CLcr
50-79 mL/min; n=27) [see Dosage
and Administration (2.1), Use in
Specific Populations (8.7)].
Drug Interaction Studies
Effect
of Strong Inhibitors or Inducers of
CYP3A4 on Eribulin: The
effect of a strong CYP3A4 inhibitor and a P-gp inhibitor, ketoconazole, on the
PK of eribulin was studied in a crossover trial of 12 patients with advanced
solid tumors. No clinically relevant PK interaction was observed when Halaven
was administered with or without ketoconazole (the geometric mean ratio of the
AUC: 0.97; 90% CI: 0.83, 1.12).
The effect of a CYP3A4
inducer, rifampin, on the PK of eribulin was studied in a crossover trial of 14
patients with advanced solid tumors. No clinically relevant PK interaction was
observed when Halaven was administered with or without rifampin (the geometric
mean ratio of the AUC: 1.10; 90 CI%: 0.91, 1.34).
Effect of Eribulin on CYP
Substrates: Eribulin shows no induction potential for CYP1A, CYP2B6,
CYP2C9, CYP2C19, and CYP3A in primary human hepatocytes. Eribulin inhibits
CYP3A4 activity in human liver microsomes, but it is unlikely that eribulin
will substantially increase the plasma levels of CYP3A4 substrates. No
significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP2E1 was
detected with eribulin concentrations up to 5 μM in pooled human liver
microsomes. In vitro drug interaction studies indicate that eribulin does not
inhibit drugs that are substrates of these enzymes and it is unlikely that
eribulin will affect plasma levels of drugs that are substrates of CYP enzymes.
Effect
of Transporters on Eribulin: In vitro data suggest that eribulin
at clinically relevant concentrations is a substrate of P-gp, but is not a
substrate of breast cancer resistance protein (BCRP), multidrug resistance
proteins (MRP2, MRP4), bile salt extrusion pump (BSEP), organic anion
transporting polypeptides (OATP1B1, OATP1B3), organic anion transporters (OAT1,
OAT3), organic cation transporters (OCT1, OCT2), or multidrug and toxin
extrusion 1 (MATE1).
Effect
of Eribulin on Transporters: In
vitro data suggest that eribulin at clinically relevant concentrations may
inhibit P-gp, but does not inhibit BCRP, OATP1B1, OCT1, OAT1, OAT3, or MATE1.
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have
not been conducted with eribulin mesylate. Eribulin mesylate was not
mutagenic in in vitro bacterial
reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma
mutagenesis assays, and was clastogenic in an in
vivo rat bone marrow micronucleus assay.
Fertility studies have not
been conducted with eribulin mesylate in humans or animals; however,
nonclinical findings in repeat-dose dog and rat toxicology studies suggest that
male fertility may be compromised by treatment with eribulin mesylate.
Rats exhibited testicular toxicity (hypocellularity of seminiferous
epithelium with hypospermia/aspermia) following dosing with eribulin mesylate
at or above 0.43 times the recommended human dose (based on body
surface area) given once weekly for 3 weeks, or at or above 0.21 times the
recommended human dose (based on body surface area) given once weekly for 3 out
of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in
dogs given 0.64 times the recommended human dose (based on body surface area)
weekly for 3 out of 5 weeks, repeated for 6 cycles.
CLINICAL STUDIES
14.1 Metastatic Breast Cancer
Study 1 was an open-label,
randomized, multicenter trial of 762 patients with metastatic breast cancer who
received at least two chemotherapeutic regimens for the treatment of metastatic
disease and experienced disease progression within 6 months of their last
chemotherapeutic regimen. Patients were required to receive prior
anthracycline- and taxane- based chemotherapy for adjuvant or metastatic
disease. Patients were randomized (2:1) to receive Halaven (n=508) or a single
agent therapy selected prior to randomization (control arm, n=254).
Randomization was stratified by geographic region, HER2/neu status, and prior
capecitabine exposure. Halaven was administered at a dose of 1.4 mg/m2 on
Days 1 and 8 of a 21-day cycle. Halaven-treated patients received a median of 5
cycles (range: 1 to 23 cycles) of therapy. Control arm therapy
consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18%
capecitabine, 16% taxane, 9% anthracycline, 10% other chemotherapy), and 3%
hormonal therapy. The main efficacy outcome was overall survival.
Patient demographic and baseline
characteristics were comparable between the treatment arms. The median age was
55 (range: 27 to 85 years) and 92% were White. Sixty-four percent of patients
were enrolled in North America/Western Europe/Australia, 25% in Eastern
Europe/Russia, and 11% in Latin America/South Africa. Ninety-one percent
of patients had a baseline ECOG performance status of 0 or 1. Tumor prognostic
characteristics, including estrogen receptor status (positive: 67%, negative:
28%), progesterone receptor status (positive: 49%, negative: 39%), HER2/neu
receptor status (positive: 16%, negative: 74%), triple negative status
(ER-, PR-, HER2/neu-: 19%), presence of visceral disease (82%, including 60%
liver and 38% lung) and bone disease (61%), and number of sites of metastases (greater
than two: 50%), were also similar in the Halaven and control arms. Patients
received a median of four prior chemotherapy regimens in both arms.
In Study 1, a statistically
significant improvement in overall survival was observed in patients randomized
to the Halaven arm compared to the control arm (see Table 5). An updated,
unplanned survival analysis, conducted when 77% of events had been observed
(see Figure 1), was consistent with the primary analysis. In patients
randomized to Halaven, the objective response rate by the RECIST criteria was
11% (95% CI: 8.6%, 14.3%) and the median response duration was
4.2 months (95% CI: 3.8, 5.0 months).
Table 5: Comparison of Overall Survival
in Halaven and Control Arm - Study 1
|
|
Overall Survival
|
Halaven
(n=508)
|
Control Arm
(n=254)
|
|
Primary survival analysis
|
|
Number
of deaths
|
274
|
148
|
|
Median,
months (95% CI)
|
13.1 (11.8, 14.3)
|
10.6 (9.3, 12.5)
|
|
Hazard
Ratio (95% CI)a
|
0.81 (0.66, 0.99)
|
|
P valueb
|
0.041
|
|
Updated survival analysis
|
|
Number
of deaths
|
386
|
203
|
|
Median,
months (95% CI)
|
13.2 (12.1, 14.4)
|
10.6 (9.2, 12.0)
|
|
CI = confidence
interval
a Based on Cox proportional hazards model stratified by
geographic region, HER2 status, and prior capecitabine therapy.
b Based on a log-rank test stratified
by geographic region, HER2 status, and prior capecitabine therapy.
|
Figure 1: Updated Overall Survival Analysis for Study 1
14.2 Liposarcoma
The efficacy and safety of
Halaven were evaluated in Study 2, an open-label, randomized (1:1),
multicenter, active-controlled trial. Eligible patients were required to
have unresectable, locally advanced or metastatic liposarcoma or
leiomyosarcoma, at least two prior systemic chemotherapies (one of which must
have included an anthracycline), and disease progression within 6 months of the
most recent chemotherapy regimen. Patients were randomized to Halaven 1.4
mg/m2 administered
intravenously on Days 1 and 8 of a 21-day cycle or to dacarbazine at a dose
of 850 mg/m2, 1000 mg/m2, or 1200 mg/m2 administered intravenously every 21 days (dacarbazine
dose was selected by the investigator prior to randomization). Treatment
continued until disease progression or unacceptable toxicity. Randomization
was stratified by histology (liposarcoma or leiomyosarcoma), number of prior
therapies (2 vs. > 2), and geographic region (U.S. and Canada vs.
Western Europe, Australia, and Israel vs. Eastern Europe, Latin America, and
Asia). The major efficacy outcome measure was overall survival (OS).
Additional efficacy outcome measures were progression-free survival (PFS) and
confirmed objective response rate (ORR) as assessed by the investigator
according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Patients
in the dacarbazine arm were not offered Halaven at the time of disease
progression.
A total of 446 patients were
randomized, 225 to the Halaven arm and 221 to the dacarbazine arm. The
median age was 56 years (range: 24 to 83); 33% were male; 73% were
White; 44% had ECOG performance status (PS) 0 and 53% had ECOG PS 1; 68%
had leiomyosarcoma and 32% had liposarcoma; 39% were enrolled in U.S. and
Canada (Region 1) and 46% were enrolled in Western Europe, Australia, and
Israel (Region 2); and 47% received more than two prior systemic
chemotherapies. The most common (>40%) prior systemic chemotherapies
were doxorubicin (90%), ifosfamide (62%), gemcitabine (59%), trabectedin (50%),
and docetaxel (48%).
Of the 143 patients with
liposarcoma, the median age was 55 years (range: 32 to 83); 62% were male, 72%
were White; 41% had ECOG PS of 0 and 53% had ECOG PS of 1; 35% were enrolled in
Region 1 and 51% were enrolled in Region 2; and 44% received more than two
prior systemic chemotherapies. The distribution of subtypes of
liposarcoma, based on local histologic assessment, were 45% dedifferentiated,
37% myxoid/round cell, and 18% pleomorphic.
Study 2 demonstrated a
statistically significant improvement in OS in patients randomized to Halaven
compared with dacarbazine (see Table 6). There was no significant
difference in progression-free survival in the overall population. Treatment
effects of Halaven were limited to patients with liposarcoma based on
pre-planned, exploratory subgroup analyses of OS and PFS (see Tables 6 and
7 and Figure 2). There was no evidence of efficacy of Halaven in patients
with advanced or metastatic leiomyosarcoma in Study 2 (see Table 7).
Table 6: Efficacy Results for the
Liposarcoma Stratum and All Patients* in Study 2a
|
|
|
Liposarcoma
Stratum
|
All Patients*
|
|
|
Halaven
(n=71)
|
Dacarbazine
(n=72)
|
Halaven
(n=225)
|
Dacarbazine
(n=221)
|
|
Overall survival
|
|
Deaths,
n (%)
|
52 (73)
|
63 (88)
|
173 (77)
|
179 (81)
|
|
Median,
months
(95% CI)
|
15.6
(10.2, 18.6)
|
8.4
(5.2, 10.1)
|
13.5
(11.1, 16.5)
|
11.3
(9.5, 12.6)
|
|
Hazard
ratio (HR)
(95% CI)
|
0.51
(0.35, 0.75)
|
0.75
(0.61, 0.94)
|
|
Stratified
log-rank p value
|
N/A†
|
0.011
|
|
Progression-free survival
|
|
Events,
n (%)
|
57 (80)
|
59 (82)
|
194 (86)
|
185 (84)
|
|
Disease
progression
|
53
|
52
|
180
|
170
|
|
Death
|
4
|
7
|
14
|
15
|
|
Median,
months
(95% CI)
|
2.9
(2.6, 4.8)
|
1.7
(1.4, 2.6)
|
2.6
(2.0, 2.8)
|
2.6
(1.7, 2.7)
|
|
HR
(95% CI)
|
0.52
(0.35, 0.78)
|
0.86
(0.69, 1.06)
|
|
Objective response rate
|
|
Objective
response rate (%)
(95% CI)
|
1.4
(0, 7.6)
|
0
(0, 4.2)
|
4.0
(1.8, 7.5)
|
5.0
(2.5, 8.7)
|
a Efficacy data from one study site enrolling six patients
were excluded.
*All patients = liposarcoma and leiomyosarcoma.
† N/A =
not applicable
Figure 2: Kaplan-Meier Curves of Overall Survival in the Liposarcoma
Stratum in Study 2
Table 7: Efficacy Results for the
Leiomyosarcoma Stratum in Study 2a
|
|
|
Leiomyosarcoma
Stratum
|
|
|
Halaven
(n=154)
|
Dacarbazine
(n=149)
|
|
Overall survival
|
|
Deaths,
n (%)
|
121 (79)
|
116 (78)
|
|
Median,
months
(95% CI)
|
12.8
(10.3, 14.8)
|
12.3
(11.0, 15.1)
|
|
HR
(95% CI)
|
0.90 (0.69, 1.18)
|
|
Progression-free survival
|
|
Events,
n (%)
|
137 (89)
|
126 (85)
|
|
Disease
progression
|
127
|
118
|
|
Death
|
10
|
8
|
|
Median,
months
(95% CI)
|
2.2
(1.5, 2.7)
|
2.6
(2.2, 2.9)
|
|
HR
(95% CI)
|
1.05 (0.81, 1.35)
|
|
Objective
response rate (%)
(95% CI)
|
5.2
(2.3, 10)
|
7.4
(3.7, 12.8)
|
a Efficacy data from one
study site enrolling six patients were excluded.
HOW SUPPLIED/STORAGE
AND HANDLING
NDC
62856-389-01
Injection:
1 mg/2 mL, in a single-use vial. One vial per carton.
Store
at 25°C (77°F); excursions permitted to 15° – 30° C (59° - 86° F). Do not
freeze. Store the vials in their original cartons.
17 PATIENT
COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient
Information).
Neutropenia
Advise patients to contact
their health care provider for a fever of 100.5°F or greater or other signs or
symptoms of infection such as chills, cough, or burning or pain on
urination [see Warnings
and Precautions (5.1)].
Peripheral
Neuropathy
Advise patients to inform
their healthcare providers of new or worsening numbness, tingling and pain in
their extremities [see Warnings
and Precautions (5.2)].
Embryo-Fetal
Toxicity
·
Advise females of reproductive
potential of the potential risk to a fetus and to inform their healthcare
provider of a known or suspected pregnancy [see Warnings
and Precautions (5.3), Use in
Specific Populations (8.1)].
·
Advise females of reproductive
potential to use effective contraception during treatment with Halaven and for
at least 2 weeks after the final dose [see Use in
Specific Populations (8.3)].
·
Advise males with female
partners of reproductive potential to use effective contraception during treatment with Halaven and for 3.5
months following the final dose [seeUse in
Specific Populations (8.3)].
Lactation
Advise women not to breastfeed
during treatment with Halaven and for 2 weeks after the final dose [see Use in Specific Populations
(8.2)].
Distributed by:
Eisai Inc.
Woodcliff Lake, NJ 07677
© 2016 Eisai Inc.
|
PATIENT INFORMATION
Halaven® (HAL-ih-ven)
(eribulin mesylate)
injection, for intravenous use
|
|
What is the most important information I should know about Halaven?
Halaven can cause serious side effects, including:
· Low white blood cell count (neutropenia).
This can lead to serious infections that could lead to death.
Your healthcare provider will check your blood cell counts before you
receive each dose of Halaven and during treatment. Call your
healthcare provider right away if you develop any of these symptoms of
infection:
° fever (temperature above 100.5°F)
° chills
° cough
° burning or pain when you urinate
· Numbness, tingling, or pain in your hands or feet (peripheral neuropathy).
Peripheral neuropathy is common with Halaven and sometimes can be
severe. Tell your healthcare provider if you have new or worsening
symptoms of peripheral neuropathy.
· Your
healthcare provider may delay, decrease your dose, or stop treatment with
Halaven if you have side effects.
See “What are possible side effects of Halaven?” for
more information about side effects.
|
|
What is Halaven?
Halaven is a prescription medicine used to treat people with:
· Breast
cancer
° that has spread to other parts of the body, and
° who have already received certain types of anticancer medicines after
the cancer has spread
· Liposarcoma
° that cannot be treated with surgery or has spread to other parts of
the body, and
° who have received treatment with a certain
type of anticancer medicine
It is not known
if Halaven is safe and effective in children under 18 years of age.
|
|
|
|
Before you receive Halaven, tell your healthcare provider about all of
your medical conditions, including if
you:
· have
liver or kidney problems
· have
heart problems, including a problem called congenital long QT syndrome
· have
low potassium or low magnesium in your blood
· are
pregnant or plan to become pregnant. Halaven can harm your unborn baby.
Tell your healthcare provider right away if you become pregnant or
think you are pregnant during treatment with Halaven.
° Females who are able to become pregnant
should use an effective birth control during treatment with Halaven and for
at least 2 weeks after the final dose of Halaven.
° Males should use an effective form of
birth control when having sex with female partners who are able to become
pregnant during treatment with Halaven and for 3 1/2 months (14 weeks) after
the final dose of Halaven.
· are
breastfeeding or plan to breastfeed. It is not known if Halaven passes into
your breast milk. Do not breastfeed during treatment with Halaven and
for 2 weeks after the final dose of Halaven.
Tell your healthcare provider about all the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements.
|
|
How will I receive Halaven?
· Halaven
is given by intravenous (IV) injection in your vein.
· Halaven
is given in “cycles” of treatment, with each cycle lasting 21 days.
· Halaven
is usually given on day 1 and day 8 of a treatment cycle.
|
|
What are the possible side effects of Halaven?
Halaven may cause serious side effects, including:
· See
“What is the most important information I should know about
Halaven?”
· Halaven can cause changes in your heartbeat
(called QT prolongation). This can cause irregular
heartbeats. Your healthcare provider may do heart monitoring
(electrocardiogram or ECG) or blood tests during your treatment with Halaven
to check for heart problems.
The most common
side effects of Halaven in people with breast cancer include:
· low
white blood cell count (neutropenia)
· low
red blood cell count (anemia)
· weakness
or tiredness
· hair
loss (alopecia)
· nausea
· constipation
The most common
side effects of Halaven in people with liposarcoma include:
· tiredness
· nausea
· hair
loss (alopecia)
· constipation
· stomach
pain
· fever
Your healthcare
provider will do blood tests before and during treatment while you are taking
Halaven. The most common changes to blood tests in people with liposarcoma
include:
|
|
· low
white blood cell count (neutropenia)
· decreased
blood levels of potassium or calcium
Tell your
healthcare provider about any side effect that bothers you or that does not
go away.
These are not all the possible side effects of Halaven. Call your
doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088.
|
|
General information about Halaven
Medicines are sometimes prescribed for purposes other than those listed in a
Patient Information leaflet. You can ask your pharmacist or healthcare
provider for information about Halaven that is written for health
professionals.
|
|
What are the ingredients in Halaven?
Active Ingredient: eribulin
mesylate
Inactive Ingredients: ethanol,
water
Halaven® is a registered trademark used by
Eisai Inc. under license from Eisai R&D Management Co., Ltd.
Distributed by: Eisai Inc. Woodcliff Lake, NJ 07677
For more information, go to www.Halaven.com or call Eisai Inc. at
1-877-873-4724. If you would like a leaflet with larger printing, please
contact Eisai Inc. at 1-877-873-4724.
|
This Patient Information has
been approved by the U.S. Food and Drug Administration.
Revised: 01/2016
PRINCIPAL
DISPLAY PANEL
NDC 62856-389-01
Halaven™
(eribulin mesylate) Injection
1 mg/2 mL
(0.5 mg/mL)
For Intravenous Use
|
Halaven eribulin mesylate injection
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:62856-389
|
|
Route of
Administration
|
INTRAVENOUS
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
ERIBULIN MESYLATE (ERIBULIN)
|
ERIBULIN
MESYLATE
|
0.5 mg
in 1 mL
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
ALCOHOL
|
|
|
WATER
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:62856-389-01
|
1 VIAL in 1
CARTON
|
|
|
1
|
|
2 mL in 1 VIAL
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA201532
|
11/15/2010
|
|
|
|
Labeler - Eisai Inc. (831600833)
|
|
Revised:
12/2017
Eisai Inc.
