Halaven

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

HALAVEN 0.44 mg/ml solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One ml contains eribulin mesilate equivalent to 0.44 mg eribulin.
Each 2 ml vial contains eribulin mesilate equivalent to 0.88 mg eribulin.
Each 3 ml vial contains eribulin mesilate equivalent to 1.32 mg eribulin.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection (injection).

Clear, colourless aqueous solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

HALAVEN is indicated for the treatment of adult patients with locally advanced or metastatic breast 
cancer who have progressed after at least one chemotherapeutic regimen for advanced disease (see 
section 5.1). Prior therapy should have included an anthracycline and a taxane in either the adjuvant or 
metastatic setting unless patients were not suitable for these treatments.

HALAVEN is indicated for the treatment of adult patients with unresectable liposarcoma who have 
received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease 
(see section 5.1).

4.2 Posology and method of administration

HALAVEN should only be administered under the supervision of a qualified physician experienced in 
the appropriate use of cytotoxic medicinal products.

Posology

The recommended dose of eribulin as the ready to use solution is 1.23 mg/m2 which should be 
administered intravenously over 2 to 5 minutes on Days 1 and 8 of every 21-day cycle. 

Please note:
In the EU the recommended dose refers to the base of the active substance (eribulin). Calculation of 
the individual dose to be administered to a patient must be based on the strength of the ready to use 
solution that contains 0.44 mg/ml eribulin and the dose recommendation of 1.23 mg/m2. The dose 
reduction recommendations shown below are also shown as the dose of eribulin to be administered 
based on the strength of the ready to use solution.

In the pivotal trials, the corresponding publications and in some other regions e.g. the United States
and Switzerland, the recommended dose is based on the salt form (eribulin mesilate).

Patients may experience nausea or vomiting. Antiemetic prophylaxis including corticosteroids should 
be considered.



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Dose delays during therapy

The administration of HALAVEN should be delayed on Day 1 or Day 8 for any of the following:
- Absolute neutrophil count (ANC) < 1 x 109/l
- Platelets < 75 x 109/l
- Grade 3 or 4 non-hematological toxicities.

Dose reduction during therapy

Dose reduction recommendations for retreatment are shown in the following table. 
Dose reduction recommendations

Adverse reaction after previous HALAVEN administration Recommended dose of 
eribulin

Haematological:
ANC < 0.5 x 109/l lasting more than 7 days 

0.97 mg/m2

ANC < 1 x 109/l neutropenia complicated by fever or 
infection
Platelets < 25 x 109/l thrombocytopenia 
Platelets < 50 x 109/l thrombocytopenia complicated by 
haemorrhage or requiring blood or platelet transfusion

Non-haematological:
Any Grade 3 or 4 in the previous cycle

Reoccurrence of any haematological or non-haematological 
adverse reactions as specified above

Despite reduction to 0.97 mg/m2 0.62 mg/m2

Despite reduction to 0.62 mg/m2 Consider discontinuation

The dose of eribulin should not be re-escalated after it has been reduced.

Patients with hepatic impairment

Impaired liver function due to metastases
The recommended dose of eribulin in patients with mild hepatic impairment (Child-Pugh A) is 
0.97 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. The 
recommended dose of eribulin in patients with moderate hepatic impairment (Child-Pugh B) is 
0.62 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle.
Severe hepatic impairment (Child-Pugh C) has not been studied but it is expected that a more marked 
dose reduction is needed if eribulin is used in these patients.

Impaired liver function due to cirrhosis
This patient group has not been studied. The doses above may be used in mild and moderate 
impairment but close monitoring is advised as the doses may need readjustment.

Patients with renal impairment

Some patients with moderately or severely impaired renal function (creatinine clearance <50 ml/min) 
may have increased eribulin exposure and may need a reduction of the dose. For all patients with renal 
impairment, caution and close safety monitoring is advised. (See section 5.2)

Elderly patients

No specific dose adjustments are recommended based on the age of the patient (see section 4.8).

Paediatric population

There is no relevant use of HALAVEN in children and adolescents for the indication of breast cancer.



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The safety and efficacy of HALAVEN in children from birth to 18 years of age have not yet been 
established in soft tissue sarcoma. No data are available.

Method of administration

HALAVEN is for intravenous use. The dose may be diluted in up to 100 ml of sodium chloride 
9 mg/ml (0.9%) solution for injection. It should not be diluted in glucose 5% infusion solution. For 
instructions on the dilution of the medicinal product before administration, see section 6.6. Good 
peripheral venous access, or a patent central line, should be ensured prior to administration. There is 
no evidence that eribulin mesilate is a vesicant or an irritant. In the event of extravasation, treatment 
should be symptomatic. For information relevant to the handling of cytotoxic medicinal products see 
section 6.6.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
- Breast-feeding

4.4 Special warnings and precautions for use

Haematology

Myelosuppression is dose dependent and primarily manifested as neutropenia (section 4.8). 
Monitoring of complete blood counts should be performed on all patients prior to each dose of 
eribulin. Treatment with eribulin should only be initiated in patients with ANC values ≥ 1.5 x 109/l and 
platelets > 100 x 109/l.

Febrile neutropenia occurred in < 5% of patients treated with eribulin. Patients experiencing febrile 
neutropenia, severe neutropenia or thrombocytopenia, should be treated according to the 
recommendations in section 4.2.

Patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x upper limit of 
normal (ULN) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia. 
Although data are limited, patients with bilirubin >1.5 x ULN also have a higher incidence of Grade 4 
neutropenia and febrile neutropenia. 

Fatal cases of febrile neutropenia, neutropenic sepsis, sepsis and septic shock have been reported.

Severe neutropenia may be managed by the use of granulocyte colony-stimulating factor (G-CSF) or 
equivalent at the physician’s discretion in accordance with relevant guidelines (see section 5.1).

Peripheral neuropathy

Patients should be closely monitored for signs of peripheral motor and sensory neuropathy. The 
development of severe peripheral neurotoxicity requires a delay or reduction of dose (see section 4.2)

In clinical trials, patients with pre-existing neuropathy greater than Grade 2 were excluded. However, 
patients with pre-existing neuropathy Grade 1 or 2 were no more likely to develop new or worsening 
symptoms than those who entered the study without the condition.

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 or
concomittant treatment with medicinal products known to prolong the QT interval, including Class Ia 
and III antiarrhythmics, and electrolyte abnormalities. Hypokalaemia, hypocalcaemia or 



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hypomagnesaemia should be corrected prior to initiating HALAVEN and these electrolytes should be 
monitored periodically during therapy. Eribulin should be avoided in patients with congenital long QT 
syndrome.

Excipients

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per dose.

4.5 Interaction with other medicinal products and other forms of interaction

Eribulin is mainly (up to 70%) eliminated through biliary excretion. The transport protein involved in 
this process is unknown. Eribulin is not a substrate of breast cancer resistance protein (BCRP), organic 
anion (OAT1, OAT3, OATP1B1, OATP1B3), multi-drug resistance-associated protein (MRP2, 
MRP4) and bile salt export pump (BSEP) transporters.

No drug-drug interactions are expected with CYP3A4 inhibitors and inducers. Eribulin exposure 
(AUC and Cmax) was unaffected by ketoconazole, a CYP3A4 and P glycoprotein (Pgp) inhibitor, and 
rifampicin, a CYP3A4 inducer.

Effects of eribulin on the pharmacokinetics of other medicines

In vitro data indicate that eribulin is a mild inhibitor of the important drug metabolising enzyme 
CYP3A4. No in vivo data are available. Caution and monitoring for adverse events is recommended 
with concomitant use of substances that have a narrow therapeutic window and that are eliminated 
mainly via CYP3A4-mediated metabolism (eg alfentanil, cyclosporine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus).

Eribulin does not inhibit the CYP enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 2E1 at relevant 
clinical concentrations.

At relevant clinical concentrations, eribulin did not inhibit BCRP, OCT1, OCT2, OAT1, OAT3, 
OATP1B1 and OATP1B3 transporter-mediated activity.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of eribulin in pregnant women. Eribulin is embryotoxic, foetotoxic, and 
teratogenic in rats. HALAVEN should not be used during pregnancy unless clearly necessary and after 
a careful consideration of the needs of the mother and the risk to the foetus.

Women of childbearing potential must be advised to avoid becoming pregnant whilst they or their 
male partner are receiving HALAVEN and have to use effective contraception during and up to 3 
months after treatment.

Breast-feeding

It is unknown whether eribulin/metabolites are excreted in human or animal breast milk. A risk to 
newborns/infants cannot be excluded and therefore HALAVEN must not be used during 
breast-feeding (see section 4.3). 

Fertility

Testicular toxicity has been observed in rats and dogs (see section 5.3). Male patients should seek 
advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility 
due to therapy with HALAVEN.



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4.7 Effects on ability to drive and use machines

HALAVEN may cause adverse reactions such as tiredness and dizziness which may lead to minor or 
moderate influence on the ability to drive or use machines. Patients should be advised not to drive or 
use machines if they feel tired or dizzy.

4.8 Undesirable effects

Summary of safety profile

The most commonly reported adverse reactions related to HALAVEN, are bone marrow suppression 
manifested as neutropenia, leucopenia, anaemia, thrombocytopenia with associated infections. New 
onset or worsening of pre-existing peripheral neuropathy has also been reported. Gastrointestinal 
toxicities, manifested as anorexia, nausea, vomiting, diarrhoea, constipation, and stomatitis are among 
reported undesirable effects. Other undesirable effects include fatigue, alopecia, increased liver 
enzymes, sepsis and musculoskeletal pain syndrome.

Tabulated list of adverse reactions

Unless otherwise noted, the table shows the incidence rates of adverse reactions observed in breast 
cancer and soft tissue sarcoma patients who received the recommended dose in Phase 2 and Phase 3 
studies. 

Frequency categories are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon 
(≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000). 
Within each frequency grouping, undesirable effects are presented in order of decreasing frequency. 
Where Grade 3 or 4 reactions occurred, the actual total frequency and the frequency of Grade 3 or 4 
reactions are given. 

System Organ 
Class

Adverse Reactions – all Grades

Very Common
(Frequency %)

Common
(Frequency %)

Uncommon
(Frequency %)

Rare or not 
known

Infections and 
infestations 

Urinary tract 
infection (8.5%) 
(G3/4: 0.7%)
Pneumonia (1.6%) 
(G3/4: 1.0%)
Oral candidiasis
Oral herpes
Upper respiratory 
tract infection 
Nasopharyngitis 
Rhinitis
Herpes zoster

Sepsis (0.5%)

(G3/4: 0.5%)a

Neutropenic sepsis

(0.2%) (G3/4: 0.2%)a

Septic Shock (0.2%) 

(G3/4:0.2%)a

Blood and 
lymphatic system
disorders

Neutropenia (53.6%) 
(G3/4: 46.0%)
Leukopenia (27.9%) 
(G3/4: 17.0%)
Anaemia (21.8%) 
(G3/4: 3.0%)

Lymphopenia (5.7%) 
(G3/4: 2.1%)
Febrile neutropenia 

(4.5%) (G3/4: 4.4%)a

Thrombocytopenia
(4.2%) (G3/4: 0.7%)

*Disseminated 
intravascular 

coagulationb



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System Organ 
Class

Adverse Reactions – all Grades

Very Common
(Frequency %)

Common
(Frequency %)

Uncommon
(Frequency %)

Rare or not 
known

Metabolism and 
nutrition 
disorders

Decreased appetite
(22.5%) (G3/4: 0.7%)d

Hypokalaemia (6.8%) 
(G3/4: 2.0%)
Hypomagnesaemia 
(2.8%) (G3/4: 0.3%)
Dehydration (2.8 %) 
(G3/4: 0.5%)d

Hyperglycaemia
Hypophosphataemia
Hypocalcaemia

Psychiatric 
disorders

Insomnia
Depression

Nervous system 
disorders

Peripheral neuropathyc

(35.9%) (G3/4: 7.3%)
Headache (17.5%) 
(G3/4: 0.7%)

Dysgeusia 
Dizziness (9.0%) 
(G3/4: 0.4%)d

Hypoaesthesia
Lethargy
Neurotoxicity

Eye disorders Lacrimation 
increased
(5.8%) (G3/4: 0.1%)d

Conjunctivitis
Ear and labyrinth 
disorders

Vertigo
Tinnitus

Cardiac disorders Tachycardia

Vascular 
disorders 

Hot flush
Pulmonary embolism 
(1.3%) (G3/4: 1.1%)a

Deep vein thrombosis

Respiratory, 
thoracic and 
mediastinal 
disorders

Dyspnoea (15.2%)a

(G3/4: 3.5%)a

Cough (15.0%) 
(G3/4: 0.5%)d

Oropharyngeal pain
Epistaxis
Rhinorrhoea

Interstitial lung 
disease (0.2%) (G3/4: 
0.1%)

Gastrointestinal 
disorders

Nausea (35.7%) 
(G3/4: 1.1%)d

Constipation (22.3%) 
(G3/4: 0.7%)d

Diarrhoea (18.7%) 
(G3/4: 0.8%)
Vomiting (18.1%) 
(G3/4: 1.0%)

Abdominal pain 
Stomatitis (11.1%) 
(G3/4: 1.0%)d

Dry mouth 
Dyspepsia (6.5%) 
(G3/4: 0.3%)d

Gastrooesophageal 
reflux disease
Abdominal distension

Mouth ulceration
Pancreatitis 

Hepatobiliary 
disorders

Aspartate 
aminotransferase 
increased (7.7%) 
(G3/4: 1.4%)d

Alanine 
aminotransferase 
increased (7.6%) 

(G3/4: 1.9%)d

Gamma glutamyl 
transferase increased 
(1.7%) (G3/4: 0.9%)d

Hyperbilirubinaemia 
(1.4%) (G3/4: 0.4%)

Hepatotoxicity 
(0.8%) (G3/4: 0.6%)



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System Organ 
Class

Adverse Reactions – all Grades

Very Common
(Frequency %)

Common
(Frequency %)

Uncommon
(Frequency %)

Rare or not 
known

Skin and 
subcutaneous 
tissue disorders

Alopecia Rash (4.9%) (G3/4: 
0.1%)
Pruritus (3.9%) 
(G3/4: 0.1%)d

Nail disorder
Night sweats
Dry skin
Erythema
Hyperhidrosis
Palmar plantar 
erythrodysaesthesia 
(1.0%) (G3/4: 0.1%)d

Angioedema **Stevens-Johnson 
syndrome/ Toxic 
epidermal 
necrolysisb

Musculoskeletal 
and connective 
tissue disorders

Arthralgia and myalgia 
(20.4%) (G3/4: 1.0%)
Back pain (12.8%) 
(G3/4: 1.5%)
Pain in extremity 
(10.0%) (G3/4: 0.7%)d

Bone pain (6.7%) 
(G3/4: 1.2%)
Muscle spasms
(5.3%) (G3/4: 0.1%)d

Musculoskeletal pain 
Musculoskeletal 
chest pain
Muscular weakness

Renal and urinary 
disorders

Dysuria Haematuria
Proteinuria
Renal failure

General disorders 
and 
administration site 
conditions

Fatigue/Asthenia
(53.2%) (G3/4 : 7.7%)
Pyrexia (21.8%) 
(G3/4: 0.7%)                      

Mucosal 
Inflammation (6.4%) 

(G3/4: 0.9%)d

Peripheral oedema 
Pain
Chills
Chest pain
Influenza like illness 

Investigations Weight decreased 

(11.4%) (G3/4: 0.4%)d

a Includes Grade 5 events.
b From spontaneous reporting
c Includes preferred terms of peripheral neuropathy, peripheral motor neuropathy, polyneuropathy, 

paraesthesia, peripheral sensory neuropathy, peripheral sensorimotor neuropathy and demyelinating 
polyneuropathy

d No Grade 4 events
* Rare
** Frequency not known

Overall, the safety profiles in the breast cancer and soft tissue sarcoma patient populations were 
similar. 

Description of selected adverse reactions

Neutropenia
The neutropenia observed was reversible and not cumulative; the mean time to nadir was 13 days and 
the mean time to recovery from severe neutropenia (< 0.5 x 109/l) was 8 days.
Neutrophil counts of < 0.5 x 109/l that lasted for more than 7 days occurred in 13% of breast cancer 
patients treated with eribulin in the EMBRACE study.
Neutropenia was reported as a Treatment Emergent Adverse Event (TEAE) in 151/404 (37.4% for all 
grades) in the sarcoma population, compared with 902/1559 (57.9% for all grades) in the breast cancer 



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population. The combined grouped TEAE and neutrophil laboratory abnormality frequencies were 
307/404 (76.0%) and 1314/1559 (84.3%), respectively. The median duration of treatment was 12.0 
weeks for sarcoma patients and 15.9 weeks for breast cancer patients.
Fatal cases of febrile neutropenia, neutropenic sepsis, sepsis and septic shock have been reported. Out 
of 1963 breast cancer and soft tissue sarcoma patients who received eribulin at the recommended dose 
in clinical trials there was one fatal event each of neutropenic sepsis (0.1%) and febrile neutropenia
(0.1%). In addition there were 3 fatal events of sepsis (0.2%) and one of septic shock (0.1%).
Severe neutropenia may be managed by the use of G-CSF or equivalent at the physician’s discretion in 
accordance with relevant guidelines. 18% and 13% of eribulin treated patients received G-CSF in the 
two phase 3 breast cancer studies (Studies 305 and 301, respectively). In the phase 3 sarcoma study 
(Study 309), 26% of the eribulin treated patients received G-CSF.
Neutropenia resulted in discontinuation in < 1% of patients receiving eribulin.

Disseminated intravascular coagulation
Cases of disseminated intravascular coagulation have been reported, typically in association with 
neutropenia and/or sepsis.

Peripheral neuropathy
In the 1559 breast cancer patients the most common adverse reaction resulting in discontinuation of 
treatment with eribulin was peripheral neuropathy (3.4%). The median time to Grade 2 peripheral 
neuropathy was 12.6 weeks (post 4 cycles). Out of the 404 sarcoma patients, 2 patients discontinued 
treatment with eribulin due to peripheral neuropathy. The median time to Grade 2 peripheral 
neuropathy was 18.4 weeks.
Development of Grade 3 or 4 peripheral neuropathy occurred in 7.4% of breast cancer patients and 
3.5% of sarcoma patients. In clinical trials, patients with pre-existing neuropathy were as likely to 
develop new or worsening symptoms as those who entered the study without the condition.
In breast cancer patients with pre-existing Grade 1 or 2 peripheral neuropathy the frequency of 
treatment-emergent Grade 3 peripheral neuropathy was 14%.

Hepatotoxicity
In some patients with normal/abnormal liver enzymes prior treatment with eribulin, increased levels of 
liver enzymes have been reported with initiation of eribulin treatment. Such elevations appeared to 
have occurred early with eribulin treatment in cycle 1 – 2 for the majority of these patients and whilst
thought likely to be a phenomenon of adaptation to eribulin treatment by the liver and not a sign of 
significant liver toxicity in most patients, hepatotoxicity has also been reported.

Special populations

Elderly population
Of the 1559 breast cancer patients treated with the recommended dose of eribulin, 283 patients
(18.2%) were ≥ 65 years of age. In the 404 sarcoma patient population, 90 patients (22.3%) treated 
with eribulin were ≥ 65 years of age. The safety profile of eribulin in elderly patients (≥ 65 years of 
age) was similar to that of patients <65 years of age except for asthenia/fatigue which showed an 
increasing trend with age. No dose adjustments are recommended for the elderly population.

Patients with hepatic impairment
Patients with ALT or AST > 3 x ULN experienced a higher incidence of Grade 4 neutropenia and 
febrile neutropenia. Although data are limited, patients with bilirubin > 1.5 x ULN also have a higher 
incidence of Grade 4 neutropenia and febrile neutropenia (see also sections 4.2 and 5.2). 

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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4.9 Overdose

In one case of overdose the patient inadvertently received 7.6 mg of eribulin (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 eribulin 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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX41

Eribulin mesilate is a microtubule dynamics inhibitor belonging to the halichondrin class of 
antineoplastic agents. It is a structurally simplified synthetic analogue of halichondrin B, a natural 
product isolated from the marine sponge Halichondria okadai.

Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and 
sequesters tubulin into non-productive 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 and irreversible mitotic blockage.

Clinical efficacy

Breast cancer

The efficacy of HALAVEN in breast cancer is primarily supported by two randomized Phase 3 
comparative studies. 
The 762 patients in the pivotal Phase 3 EMBRACE study (Study 305) had locally recurrent or 
metastatic breast cancer, and had previously received at least two and a maximum of five 
chemotherapy regimens, including an anthracycline and a taxane (unless contraindicated). Patients 
must have progressed within 6 months of their last chemotherapeutic regimen. The HER2 status of the 
patients was: 16.1% positive, 74.2% negative and 9.7% unknown, whilst 18.9% of patients were triple 
negative. They were randomized 2:1 to receive either HALAVEN, or treatment of physician’s choice 
(TPC), which consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 
16% taxane, 9% anthracycline, 10% other chemotherapy), or 3% hormonal therapy.
The study met its primary endpoint with an overall survival (OS) result that was statistically 
significantly better in the eribulin group compared to TPC at 55% of events. 
This result was confirmed with an updated overall survival analysis carried out at 77% of events.



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Study 305 - Updated Overall Survival ( ITT Population)

P
R

O
P

O
R

T
IO

N
 O

F
 P

A
T

IE
N

T
S

 A
L

IV
E

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

TIME (months)

NUMBER OF PATIENTS AT RISK

HALAVEN 508 406 274 142 54 11 0

TPC 254 178 106 61 26 5 0

By independent review, the median progression free survival (PFS) was 3.7 months for eribulin 
compared to 2.2 months for the TPC arm (HR 0.865, 95% CI: 0.714, 1.048, p=0.137). In response 
evaluable patients, the objective response rate by the RECIST criteria was 12.2% (95% CI: 9.4%, 
15.5%) by independent review for the eribulin arm compared to 4.7% (95% CI: 2.3%, 8.4%) for the
TPC arm.

The positive effect on OS was seen in both taxane-refractory and non-refractory groups of patients . In 
the OS update, the HR for eribulin versus TPC was 0.90 (95% CI: 0.71, 1.14) in favour of eribulin for 
taxane-refractory patients and 0.73 (95% CI: 0.56, 0.96) for patients not taxane-refractory. 

The positive effect on OS was seen both in capecitabine-naïve and in capecitabine pre-treated patient 
groups. The updated OS analysis showed a survival benefit for the eribulin group compared to TPC 
both in capecitabine pre-treated patients with a HR of 0.787 (95% CI: 0.645, 0.961), and for the 
capecitabine-naïve patients with a corresponding HR of 0.865 (95% CI: 0.606, 1.233). 

The second Phase 3 study in earlier line metastatic breast cancer, Study 301, was an open-label, 
randomized, study in patients (n=1102) with locally advanced or metastatic breast cancer to 
investigate the efficacy of HALAVEN monotherapy compared to capecitabine monotherapy in terms 
of OS and PFS as co-primary endpoint. Patients had previously received up to three prior 
chemotherapy regimens, including both an anthracycline and a taxane and a maximum of two for 
advanced disease, with the percentage who had received 0, 1 or 2 prior chemotherapy treatments for 
metastatic breast cancer being 20.0%, 52.0% or 27.2% respectively. The HER2 status of the patients 
was: 15.3% positive, 68.5% negative and 16.2% unknown, whilst 25.8% of patients were triple 
negative.

Efficacy Parameter HALAVEN
(n=508)

TPC
(n=254)

Overall Survival

Number of Events 386 203

Median (months) 13.2 10.5

Hazard Ratio (95% CI)a 0.805 (0.677, 0.958)

Nominal P value
(log rank)

0.014b

aCox proportional hazard
bStratified by geographic region, HER2/neu status, 

and prior capecitabine therapy.

Treatment of 
Physician’s Choice 

(TPC)

HALAVEN



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Study 301 - Overall Survival (ITT Population)
P

R
O

B
A

B
IL

IT
Y

 O
F

 S
U

R
V

IV
A

L

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

TIME (months)

NUMBER OF PATIENTS AT RISK

HALAVEN 554 530 505 464 423 378 349 320 268 243 214 193 173 151 133 119 99 77 52 38 32 26 22 15 13 9 7 2 2 0

Capecitabine 548 513 466 426 391 352 308 277 242 214 191 175 155 135 122 108 81 62 42 33 27 23 17 13 12 10 2 2 1 0

Progression free survival assessed by independent review was similar between eribulin and 
capecitabine with medians of 4.1 months vs 4.2 months (HR 1.08; [95% CI: 0.932, 1.250]) 
respectively. Objective response rate as assessed by independent review was also similar between 
eribulin and capecitabine; 11.0% (95% CI: 8.5, 13.9) in the eribulin group and 11.5% (95% CI: 8.9, 
14.5) in the capecitabine group.

The overall survival in patients in HER2 negative and HER2 positive patients in the eribulin and 
control groups in Study 305 and Study 301 is shown below:

Efficacy Parameter
Study 305 Updated Overall Survival ITT Population

HER2 Negative HER2 Positive 
HALAVEN

(n = 373)
TPC

(n = 192)
HALAVEN

(n = 83)
TPC

(n = 40)
Number of Events 285 151 66 37
Median months 13.4 10.5 11.8 8.9 

Hazard Ratio (95% CI) 0.849 (0.695, 1.036) 0.594 (0.389, 0.907)
p-value (log rank) 0.106 0.015

Efficacy Parameter
Study 301 Overall Survival ITT Population

HER2 Negative HER2 Positive 
HALAVEN

(n = 375)
Capecitabine

(n = 380)
HALAVEN

(n = 86)
Capecitabine

(n = 83)
Number of Events 296 316 73 73
Median months 15.9 13.5 14.3 17.1 
Hazard Ratio (95% CI) 0.838 (0.715, 0.983) 0.965 (0.688, 1.355)
p-value (log rank) 0.030 0.837                                     
Note: Concomitant anti-HER2 therapy was not included in Study 305 and Study 301.

Capecitabine

HALAVEN

Efficacy Parameter OS in ITT Population

HALAVEN
(n=554)

Capecitabine
(n=548)

Number of Events 446 459

Median (months) 15.9 14.5

Hazard Ratio (95% CI)a 0.879 (0.770, 1.003)

P value (log rank) 0.056b

aCox proportional hazard
bStratified by geographic region, HER2/neu status



13

Liposarcoma

In liposarcoma the efficacy of eribulin is supported by the pivotal Phase 3 sarcoma study (Study 309). 
The patients in this study (n=452) had locally recurrent, inoperable and/or metastatic soft tissue 
sarcoma of one of two subtypes – leiomyosarcoma or liposarcoma. Patients had received at least two 
prior chemotherapy regimens, one of which must have been an anthracycline (unless contraindicated).

Patients must have progressed within 6 months of their last chemotherapeutic regimen. They were 
randomized 1:1 to receive either eribulin 1.23 mg/m2 on days 1 and 8 of a 21 day cycle or dacarbazine 
850 mg/m2, 1000 mg/m2 or 1200 mg/m2 (dose determined by the investigator prior to randomization), 
every 21 days.

In Study 309, a statistically significant improvement in OS was observed in patients randomized to the 
eribulin arm compared to the control arm. This translated into a 2 month improvement in median OS 
(13.5 months for eribulin treated patients vs. 11.5 months for dacarbazine treated patients). There was 
no significant difference in progression-free survival or overall response rate between the treatment 
arms in the overall population.

Treatment effects of eribulin were limited to patients with liposarcoma (45% dedifferentiated, 37% 
myxoid/round cell and 18% pleomorphic in Study 309) based on pre-planned subgroup analyses of OS 
and PFS. There was no difference in efficacy between eribulin and dacarbazine in patients with 
advanced or metastatic leiomyosarcoma.

Study 309 
Liposarcoma Subgroup

Study 309
Leiomyosarcoma Subgroup

Study 309
ITT Population

HALAVEN
(n=71)

Dacarbazine
(n=72)

HALAVEN
(n=157)

Dacarbazine
(n=152)

HALAVEN
(n=228)

Dacarbazine
(n=224)

Overall survival
Number of 

Events
52 63 124 118 176 181

Median months 15.6 8.4 12.7 13.0 13.5 11.5

Hazard Ratio 
(95% CI)

0.511 (0.346, 0.753) 0.927 (0.714, 1.203) 0.768 (0.618, 0.954)

Nominal p-
value

0.0006 0.5730 0.0169

Progression-free survival
Number of 

Events
57 59 140 129 197 188

Median months 2.9 1.7 2.2 2.6 2.6 2.6
Hazard Ratio 
(95% CI)

0.521 (0.346, 0.784) 1.072 (0.835, 1.375) 0.877 (0.710, 1.085)

Nominal p-
value

0.0015 0.5848 0.2287



14

Study 309 - Overall Survival in the Liposarcoma Subgroup
P

R
O

B
A

B
IL

IT
Y

 O
F

 S
U

R
V

IV
A

L

Time (months)

NUMBER OF PATIENTS AT RISK:

HALAVEN 71 63 51 43 39 34 30 20 15 12 7 4 2 0

Dacarbazine 72 59 42 33 22 17 12 11 6 3 2 0 0 0

Study 309 – Progression Free Survival in the Liposarcoma Subgroup

P
R

O
B

A
B

IL
IT

Y
 O

F
 S

U
R

V
IV

A
L

Time (months)

NUMBER OF PATIENTS AT RISK:

HALAVEN 71 28 17 12 9 3 1 0

Dacarbazine 72 15 5 2 1 0 0 0

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with 
eribulin in all subsets of the paediatric population in the indication of breast cancer (see section 4.2 for 
information on paediatric use).

HALAVEN

Dacarbazine

HALAVEN

Dacarbazine



15

The European Medicines Agency has deferred the obligation to submit the results of studies with 
HALAVEN in one or more subsets of the paediatric population for the treatment of 
rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma. See section 4.2 for information 
on paediatric use.

5.2 Pharmacokinetic properties

Distribution

The pharmacokinetics of eribulin are characterized by a rapid distribution phase followed by a 
prolonged elimination phase, with a mean terminal half-life of approximately 40 h. It has a large 
volume of distribution (range of means 43 to 114 l/m2). 

Eribulin is weakly bound to plasma proteins. The plasma protein binding of eribulin (100-1000 ng/ml) 
ranged from 49% to 65% in human plasma. 

Biotransformation 

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.

Elimination

Eribulin has a low clearance (range of means 1.16 to 2.42 l/h/m2). No significant accumulation of 
eribulin is observed on weekly administration. The pharmacokinetic properties are not dose or time 
dependent in the range of eribulin doses of 0.22 to 3.53 mg/m2. 

Eribulin is eliminated primarily by biliary excretion. The transport protein involved in the excretion is 
presently unknown. Preclinical in vitro studies indicate that eribulin is transported by Pgp. However it 
has been shown that at clinically relevant concentrations eribulin is not a Pgp inhibitor in vitro. 
Additionally, in vivo, concomitant administration of ketoconazole, a Pgp inhibitor, has no effect on 
eribulin exposure (AUC and Cmax). In vitro studies have also indicated that eribulin is not a substrate 
for OCT1.

After administration of 14C-eribulin to patients, approximately 82% of the dose was eliminated in 
faeces and 9% in urine indicating that renal clearance is not a significant route of eribulin elimination.

Unchanged eribulin represented most of the total radioactivity in faeces and urine.

Hepatic impairment

A study evaluated the pharmacokinetics of eribulin in patients with mild (Child-Pugh A; n=7) and 
moderate (Child-Pugh B; n=4) hepatic impairment due to liver metastases. Compared to patients with 
normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 3-fold in patients with mild 
and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 0.97 mg/m2

to patients with mild hepatic impairment and 0.62 mg/m2 to patients with moderate hepatic impairment 
resulted in a somewhat higher exposure than after a dose of 1.23 mg/m2 to patients with normal 
hepatic function. HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh 
C). There is no study in patients with hepatic impairment due to cirrhosis. See section 4.2 for dosage 
recommendation.

Renal impairment

Increased eribulin exposure was seen in some patients with moderately or severely impaired renal 
function, with high between-subject variability. The pharmacokinetics of eribulin were evaluated in a 
Phase 1 study in patients with normal renal function (Creatinine clearance: ≥ 80 ml/min; n=6), 



16

moderate (30-50 ml/min; n=7) or severe (15-<30 ml/min; n=6) renal impairment. Creatinine clearance 
was estimated with the Cockcroft-Gault formula. A 1.5-fold (90% CI: 0.9-2.5) higher dose-normalised 
AUC(0-inf) was observed in patients with moderate and severe renal impairment. See section 4.2 for 
treatment recommendations.

5.3 Preclinical safety data

Eribulin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test). Eribulin was 
positive in the mouse lymphoma mutagenesis assay and was clastogenic in the in vivo rat 
micronucleus assay. 

No carcinogenicity studies have been conducted with eribulin.

A fertility study was not conducted with eribulin, but based on non-clinical findings in repeated-dose 
studies where testicular toxicity was observed in both rats (hypocellularity of seminiferous epithelium 
with hypospermia/aspermia) and dogs, male fertility may be compromised by treatment with eribulin.
An embryofoetal development study in rat confirmed the developmental toxicity and teratogenic 
potential of eribulin. Pregnant rats were treated with eribulin mesilate equivalent to 0.009, 0.027, 
0.088 and 0.133 mg/kg eribulin at gestation days 8, 10 and 12. Dose related increased number of 
resorptions and decreased foetal weight were observed at doses ≥ 0.088 mg/kg and increased incidence 
of malformations (absence of lower jaw, tongue, stomach and spleen) was recorded at 0.133 mg/kg.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Ethanol anhydrous
Water for injections
Hydrochloric acid (for pH-adjustment)
Sodium hydroxide (for pH-adjustment)

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vials

5 years.

In-use shelf life

From a microbiological point of view unless the method of opening precludes the risk of microbial 
contamination the product should be used immediately. If not used immediately, in-use storage times 
and conditions are the responsibility of the user. 

If not used immediately HALAVEN as the undiluted solution in a syringe should not normally be 
stored longer than 4 hours at 25°C and ambient lighting, or 24 hours at 2°C - 8°C.

Diluted solutions of HALAVEN (0.018 mg/ml to 0.18 mg/ml eribulin in sodium chloride 9 mg/ml 
(0.9%)) solution for injection should not be stored longer than 24 hours at 2°C - 8°C, unless dilution 
has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage



17

This medicinal product does not require any special storage conditions.

For storage conditions after first opening or dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

5 ml type I glass vial, with teflon-coated, butyl rubber stopper and flip-off aluminium over seal, 
containing 2 ml of solution.
5 ml type I glass vial, with teflon-coated, butyl rubber stopper and flip-off aluminium over seal, 
containing 3 ml of solution.

The pack sizes are cartons of 1 or 6 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

HALAVEN is a cytotoxic anticancer medicinal product and, as with other toxic compounds, caution 
should be exercised in its handling. The use of gloves, goggles, and protective clothing is 
recommended. If the skin comes into contact with the solution it should be washed immediately and 
thoroughly with soap and water. If it contacts mucous membranes, the membranes should be flushed 
thoroughly with water. HALAVEN should only be prepared and administered by personnel 
appropriately trained in handling of cytotoxic agents. Pregnant staff should not handle HALAVEN.

Using aseptic technique HALAVEN can be diluted up to 100 ml with sodium chloride 9 mg/ml (0.9%) 
solution for injection. Following administration, it is recommended that the intravenous line be flushed 
with sodium chloride 9 mg/ml (0.9%) solution for injection to ensure administration of the complete 
dose. It must not be mixed with other medicinal products and should not be diluted in glucose 5% 
infusion solution.

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 

7. MARKETING AUTHORISATION HOLDER

Eisai GmbH
Edmund-Rumpler-Straße 3    
60549 Frankfurt am Main
Germany
e-mail: medinfo_de@eisai.net

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/11/678/001-004



18

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17 March 2011
Date of latest renewal: 19 November 2015

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.



19

ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT



20

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

Eisai Manufacturing Ltd.
European Knowledge Centre
Mosquito Way
Hatfield, Herts AL10 9SN
United Kingdom

Or

Eisai GmbH
Edmund-Rumpler-Straße 3    
60549 Frankfurt am Main
Germany

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2).

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic Safety Update Reports 

The requirements for submission of periodic safety update reports for this medicinal product are 
set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of 
Directive 2001/83/EC and any subsequent updates published on the European medicines web-
portal.

The marketing authorisation holder shall submit the first periodic safety update report for this 
product within 6 months following authorisation.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile 
or as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.



21

ANNEX III

LABELLING AND PACKAGE LEAFLET



22

A. LABELLING



23

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Outer carton 2ml vial

1. NAME OF THE MEDICINAL PRODUCT

HALAVEN 0.44 mg/ml solution for injection 
Eribulin 

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each 2 ml vial contains eribulin mesilate equivalent to 0.88 mg eribulin

3. LIST OF EXCIPIENTS

Ethanol anhydrous,Water for injections,Hydrochloric acid,Sodium hydroxide
See leaflet for further information

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection

1 vial of 2 ml
6 vials of 2 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Intravenous use

Read the package leaflet before use. 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children. 

7. OTHER SPECIAL WARNING(S), IF NECESSARY

CYTOTOXIC 

8. EXPIRY DATE

EXP:



24

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Eisai GmbH
Edmund-Rumpler-Straße 3    
60549 Frankfurt am Main
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/11/678/001 1 vial 
EU/1/11/678/002 6 vials

13. BATCH NUMBER

Lot:

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



25

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

Vial 2 ml vial

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

HALAVEN 0.44 mg/ml injection 
Eribulin 
IV

2. METHOD OF ADMINISTRATION 

3. EXPIRY DATE 

EXP:

4. BATCH NUMBER 

Lot:

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

Contains 0.88 mg eribulin in 2 ml

6. OTHER 



26

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Outer carton 3 ml vial

1. NAME OF THE MEDICINAL PRODUCT

HALAVEN 0.44 mg/ml solution for injection 
Eribulin 

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each 3 ml vial contains eribulin mesilate equivalent to 1.32 mg eribulin

3. LIST OF EXCIPIENTS

Ethanol anhydrous,Water for injections, Hydrochloric acid, Sodium hydroxide
See leaflet for further information

4. PHARMACEUTICAL FORM AND CONTENTS

Solution for injection

1 vial of 3 ml
6 vials of 3 ml

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Intravenous use

Read the package leaflet before use. 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children. 

7. OTHER SPECIAL WARNING(S), IF NECESSARY

CYTOTOXIC 

8. EXPIRY DATE

EXP:



27

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Eisai GmbH
Edmund-Rumpler-Straße 3    
60549 Frankfurt am Main
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/11/678/003 1 vial 
EU/1/11/678/004 6 vials

13. BATCH NUMBER

Lot:

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: 
SN: 
NN: 



28

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

Vial 3 ml vial

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

HALAVEN 0.44 mg/ml injection 
Eribulin 
IV

2. METHOD OF ADMINISTRATION 

3. EXPIRY DATE 

EXP:

4. BATCH NUMBER 

Lot:

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

Contains 1.32 mg eribulin in 3 ml

6. OTHER 



29

B. PACKAGE LEAFLET



30

Package leaflet: Information for the user

HALAVEN 0.44 mg/ml solution for injection
eribulin

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or nurse.
- If you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet. See section 4.

What is in this leaflet

1. What HALAVEN is and what it is used for 
2. What you need to know before you use HALAVEN 
3. How to use HALAVEN 
4. Possible side effects 
5. How to store HALAVEN
6. Contents of the pack and other information 

1. What HALAVEN is and what it is used for

HALAVEN contains the active substance eribulin and is an anti-cancer medicine which works by 
stopping the growth and spread of cancer cells.

It is used in adults for locally advanced or metastatic breast cancer (breast cancer that has spread 
beyond the original tumour) when at least one other therapy has been tried but has lost its effect.

It is also used in adults for advanced or metastatic liposarcoma (a type of cancer that arises from fat 
tissue) when previous therapy has been tried but has lost its effect.

2. What you need to know before you use HALAVEN

Do not use HALAVEN:
- if you are allergic to eribulin mesilate or any of the other ingredients of this medicine (listed in 

section 6). 
- if you are breast-feeding

Warnings and precautions
Talk to your doctor or nurse before using HALAVEN:
- if you have liver problems
- if you have a fever or an infection
- if you experience numbness, tingling, prickling sensations, sensitivity to touch or muscle 

weakness
- if you have heart problems

If any of these affects you, tell your doctor who may wish to stop treatment or reduce the dose.

Children and adolescents

Halaven is not recommended for children aged under 18 with paediatric sarcomas as it is not yet 
known how well it works in this age group.



31

Other medicines and HALAVEN
Tell your doctor if you are using, have recently used or might use any other medicines.

Pregnancy, breast-feeding and fertility
HALAVEN may cause serious birth defects and should not be used if you are pregnant unless it is 
thought clearly necessary after carefully considering all the risk to you and the baby. It may also cause 
future permanent fertility problems in men if they take it and they should discuss this with their doctor 
before starting treatment. Women of childbearing age should use effective contraception during and up 
to 3 months after treatment with HALAVEN.

HALAVEN must not be used during breast-feeding because of the possibility of risk to the child.

Driving and using machines
HALAVEN may cause side effects such as tiredness (very common) and dizziness (common). Do not 
drive or use machines if you feel tired or dizzy.

HALAVEN contains ethanol (alcohol)
This medicine contains small amounts of ethanol (alcohol), less than 100 mg in a vial.

3. How to use HALAVEN

HALAVEN will be given to you by a doctor or nurse as an injection into a vein, over a period of 2 to 5 
minutes. The dose you will receive is based on your body surface area (expressed in squared metres, 
or m2) which is calculated from your weight and height. The usual dose of HALAVEN is 1.23 mg/m2, 
but this may be adjusted by your doctor based on your blood test results or other factors. To ensure 
that the whole dose of HALAVEN is given it is recommended that a saline solution is flushed into the 
vein after HALAVEN is given.

How often will you be given HALAVEN?
HALAVEN is usually given on Days 1 and 8 of every 21-day cycle. Your doctor will determine how 
many cycles of treatment you should receive. Depending on the results of your blood tests, the doctor 
may need to delay administration of the medicine until the blood tests return to normal. The doctor 
may also then decide to reduce the dose you are given.

If you have any further questions about the use of this medicine, ask your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

If you experience any of the following serious symptoms, stop taking HALAVEN and seek medical 
attention straightaway:

- Fever, with a racing heart beat, rapid shallow breathing, cold, pale, clammy or mottled skin 
and/or confusion. These may be signs of a condition called sepsis – a severe and serious
reaction to an infection. Sepsis is uncommon (may affect up to 1 in 100 people) and can be life-
threatening and may result in death.

- Any difficulty breathing, or swelling of your face, mouth, tongue or throat. These could be signs 
of an uncommon allergic reaction (may affect up to 1 in 100 people).

- Serious skin rashes with blistering of the skin, mouth, eyes and genitals. These may be signs of 
a condition called Stevens Johnson syndrome/toxic epidermal necrolysis. The frequency of this 
condition is not known but it can be life-threatening.



32

Other side effects:

Very common side effects (may affect more than 1 in 10 people) are:

- Decrease in the number of white blood cells or red blood cells
- Tiredness or weakness
- Nausea, vomiting, constipation, diarrhoea
- Numbness, tingling or prickling sensations
- Fever
- Loss of appetite, weight loss
- Difficulty breathing, cough
- Pain in the joints, muscles and back
- Headache
- Hair loss

Common side effects (may affect up to 1 in 10 people) are:

- Decrease in the number of platelets (which may result in bruising or taking longer to stop 
bleeding)

- Infection with fever, pneumonia, chills
- Fast heart rate, flushing
- Vertigo, dizziness
- Increased production of tears, conjunctivitis (redness and soreness of the surface of the eye), 

nosebleed
- Dehydration, dry mouth, cold sores, oral thrush, indigestion, heartburn, abdominal pain or 

swelling
- Swelling of soft tissues, pains (in particular chest, back and bone pain), muscle spasm or 

weakness
- Mouth, respiratory and urinary tract infections, painful urination
- Sore throat, sore or runny nose, flu-like symptoms, throat pain 
- Liver function test abnormalities, altered level of sugar, bilirubin, phosphates, potassium,

magnesium or calcium in the blood
- Inability to sleep, depression, changed sense of taste
- Rash, itching, nail problems, dry or red skin
- Excessive sweating (including night sweats)
- Ringing in the ears
- Blood clots in the lungs
- Shingles
- Swelling of the skin and numbness of the hands and feet

Uncommon side effects (may affect up to 1 in 100 people) are:

- Blood clots
- Abnormal liver function tests (hepatoxicity)
- Kidney failure, blood or protein in the urine 
- Widespread inflammation of the lungs which may lead to scarring
- Inflammation of the pancreas
- Mouth ulcers

Rare side effects (may affect up to 1 in 1000 people) are:

- A serious disorder of blood clotting resulting in the widespread formation of blood clots and 
internal bleeding.



33

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 

listed in this leaflet. You can also report side effects directly via the national reporting system listed in 

Appendix V. By reporting side effects you can help provide more information on the safety of this 

medicine.

5. How to store HALAVEN

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the carton and the vial after EXP. The 
expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What HALAVEN contains

- The active substance is eribulin. Each 2 ml vial contains eribulin mesilate equivalent to 0.88 mg 
eribulin. Each 3 ml vial contains eribulin mesilate equivalent to 1.32 mg eribulin.

- The other ingredients are ethanol and water for injections, with hydrochloric acid and sodium 
hydroxide possibly present in very small amounts.

What HALAVEN looks like and contents of the pack 

HALAVEN is a clear, colourless aqueous solution for injection provided in glass vials containing 2 ml 
or 3ml of solution. Each carton contains either 1 or 6 vials.

Marketing Authorisation Holder
Eisai GmbH
Edmund-Rumpler-Straße 3    
60549 Frankfurt am Main
Germany
e-mail: medinfo_de@eisai.net

Manufacturer
Eisai Manufacturing Limited
European Knowledge Centre
Mosquito Way
Hatfield
Hertfordshire
AL10 9SN
United Kingdom.

Or

Eisai GmbH
Edmund-Rumpler-Straße 3    
60549 Frankfurt am Main
Germany

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


34

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 

België/Belgique/Belgien

Eisai SA/NV

Tél/Tel: +32 (0)800 158 58

Lietuva

Ewopharma AG

Tel: +370 5 248 73 50

България

Ewopharma AG

Teл: +359 2 962 12 00

Luxembourg/Luxemburg

Eisai SA/NV

Tél/Tel: + 32 (0)800 158 58

(Belgique/Belgien)

Česká republika

Eisai GesmbH organizační složka

Tel.: + 420 242 485 839

Magyarország

Ewopharma Hungary Ltd.

Tel: +36 1 200 46 50

Danmark

Eisai AB

Tlf: + 46 (0) 8 501 01 600 

(Sverige)

Malta

Associated Drug Company Ltd. 

Tel: + 356 22778000

Deutschland

Eisai GmbH

Tel: + 49 (0) 69 66 58 50

Nederland

Eisai B.V.

Tél/Tel: + 31 (0) 900 575 3340

Eesti

Ewopharma AG

Tel. +370 5 248 73 50

Norge

Eisai AB

Tlf: + 46 (0) 8 501 01 600

(Sverige)

Ελλάδα

Eisai Ltd.

Τηλ: + 44 (0)208 600 1400

(Ηνωµένο Βασίλειο)

Österreich

Eisai GesmbH

Tel: + 43 (0) 1 535 1980-0

España

Eisai Farmacéutica, S.A.

Tel: + (34) 91 455 94 55

Polska

Ewopharma AG Sp. z o.o.

Tel.: +48 (22) 620 11 71

France

Eisai SAS

Tél: + (33) 1 47 67 00 05

Portugal

Eisai Farmacêutica, Unipessoal Lda

Tel: + 351 214 875 540

Hrvatska

Ewopharma d.o.o.

Tel: +385 (0) 1 6646 563

România 

Ewopharma AG
Tel: +40 21 260 13 44

Ireland

Eisai GmbH

Tel: + 49 (0) 69 66 58 50

(Germany)

Slovenija

Ewopharma d.o.o.
Tel: +386 590 848 40

Ísland

Eisai AB

Sími: + 46 (0)8 501 01 600 

(Svíþjóð)

Slovenská republika

Eisai GesmbH organizační složka

Tel.: + 420 242 485 839

(Česká republika)



35

Italia

Eisai S.r.l.

Tel: + 39 02 5181401

Suomi/Finland

Eisai AB

Puh/Tel: + 46 (0) 8 501 01 600

(Ruotsi)

Κύπρος

Eisai Ltd.

Τηλ: +44 (0)208 600 1400

(Ηνωµένο Βασίλειο)

Sverige

Eisai AB

Tel: + 46 (0) 8 501 01 600

Latvija

Ewopharma AG

Tel: +371 677 04000

United Kingdom

Eisai Ltd.

Tel: + 44 (0)208 600 1400

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET