HALAVEN

Israel - English - Ministry of Health

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Active ingredient:
ERIBULIN AS MESILATE
Available from:
NEOPHARM SCIENTIFIC LTD
ATC code:
L01XX41
Pharmaceutical form:
SOLUTION FOR INJECTION
Composition:
ERIBULIN AS MESILATE 0.44 MG/ML
Administration route:
I.V
Prescription type:
Required
Manufactured by:
EISAI MANUFACTURING LIMITED, UK
Therapeutic group:
ERIBULIN
Therapeutic area:
ERIBULIN
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. 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.
Authorization number:
148 18 33511 01
Authorization date:
2017-04-30

לע העדוה לע העדוה לע העדוה ( הרמחה ( הרמחה ( הרמחה

עדימ עדימ עדימ ל ןולעב )תוחיטב ל ןולעב )תוחיטב ל ןולעב )תוחיטב אפור אפור אפור

ןכדועמ( ןכדועמ( ןכדועמ(

.102.50

.102.50

.102.50

:ךיראת

01/01/110/

םושיר רפסמו תילגנאב רישכת םש

:

33511

Halaven

:םושירה לעב םש

Neopharm Scientific Ltd.

ה טורפל דעוימ הז ספוט דבלב תורמחה

תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

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.

[…]

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.

[…]

[…]

System

Organ Class

Adverse Reactions – all Grades

Very Common

(Frequency %)

Common

(Frequency %)

Uncommon

(Frequency %)

Rare

Skin and

subcutaneous

tissue

disorders

Alopecia

Rash (4.9%) (G3/4:

0.1%)

Pruritus (3.9%)

(G3/4: 0.1%)

Nail disorder

Night sweats

Dry skin

Erythema

Hyperhidrosis

Palmar plantar

erythrodysaesthesia

(1.0%) (G3/4: 0.1%)

Angioedema

[…]

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%)

Nail disorder

Night sweats

Dry skin

Erythema

Hyperhidrosis

Palmar plantar

erythrodysaesthesia

(1.0%) (G3/4: 0.1%)

Angioedema

Stevens-

Johnson

syndrome/

Toxic

epidermal

necrolysis

1.

NAME OF THE MEDICINAL PRODUCT

HALAVEN

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.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for 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/m

which should be

administered intravenously over 2 to 5 minutes on Days 1 and 8 of every 21-day cycle.

Please note:

In Israel and 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/m

. 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.

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 10

Platelets < 75 x 10

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 10

/l lasting more than 7 days

0.97 mg/m

ANC < 1 x 10

/l neutropenia complicated by fever or

infection

Platelets < 25 x 10

/l thrombocytopenia

Platelets < 50 x 10

/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/m

0.62 mg/m

Despite reduction to 0.62 mg/m

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/m

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/m

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.

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

initiated in

patients with

values ≥ 1.5 x 10

/l and

platelets

> 100 x 10

Febrile neutropenia occurred in < 5% of patients treated with eribulin. Patients experiencing febrile

neutropenia,

severe

neutropenia

thrombocytopenia,

should

treated

according

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

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 C

) 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.

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%)

Neutropenic sepsis

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

Septic Shock (0.2%)

(G3/4:0.2%)

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%)

Thrombocytopenia

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

Disseminated

intravascular

coagulation

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%)

Hypokalaemia (6.8%)

(G3/4: 2.0%)

Hypomagnesaemia

(2.8%) (G3/4: 0.3%)

Dehydration (2.8 %)

(G3/4: 0.5%)

Hyperglycaemia

Hypophosphataemia

Hypocalcaemia

Psychiatric

disorders

Insomnia

Depression

Nervous system

disorders

Peripheral neuropathy

(35.9%) (G3/4: 7.3%)

Headache (17.5%)

(G3/4: 0.7%)

Dysgeusia

Dizziness (9.0%)

(G3/4: 0.4%)

Hypoaesthesia

Lethargy

Neurotoxicity

Eye disorders

Lacrimation

increased

(5.8%) (G3/4: 0.1%)

Conjunctivitis

Ear and labyrinth

disorders

Vertigo

Tinnitus

Cardiac disorders

Tachycardia

Vascular

disorders

Hot flush

Pulmonary embolism

(1.3%) (G3/4: 1.1%)

Deep vein thrombosis

Respiratory,

thoracic and

mediastinal

disorders

Dyspnoea (15.2%)

(G3/4: 3.5%)

Cough (15.0%)

(G3/4: 0.5%)

Oropharyngeal pain

Epistaxis

Rhinorrhoea

Interstitial lung

disease (0.2%) (G3/4:

0.1%)

Gastrointestinal

disorders

Nausea (35.7%)

(G3/4: 1.1%)

Constipation (22.3%)

(G3/4: 0.7%)

Diarrhoea (18.7%)

(G3/4: 0.8%)

Vomiting (18.1%)

(G3/4: 1.0%)

Abdominal pain

Stomatitis (11.1%)

(G3/4: 1.0%)

Dry mouth

Dyspepsia (6.5%)

(G3/4: 0.3%)

Gastrooesophageal

reflux disease

Abdominal distension

Mouth ulceration

Pancreatitis

Hepatobiliary

disorders

Aspartate

aminotransferase

increased (7.7%)

(G3/4: 1.4%)

Alanine

aminotransferase

increased (7.6%)

(G3/4: 1.9%)

Gamma glutamyl

transferase increased

(1.7%) (G3/4: 0.9%)

Hyperbilirubinaemia

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

Hepatotoxicity

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

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%)

Nail disorder

Night sweats

Dry skin

Erythema

Hyperhidrosis

Palmar plantar

erythrodysaesthesia

(1.0%) (G3/4: 0.1%)

Angioedema

Stevens-Johnson

syndrome/ Toxic

epidermal

necrolysis

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%)

Bone pain (6.7%)

(G3/4: 1.2%)

Muscle spasms

(5.3%) (G3/4: 0.1%)

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%)

Peripheral oedema

Pain

Chills

Chest pain

Influenza like illness

Investigations

Weight decreased

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

Includes Grade 5 events.

From spontaneous reporting

Includes preferred terms of peripheral neuropathy, peripheral motor neuropathy, polyneuropathy,

paraesthesia, peripheral sensory neuropathy, peripheral sensorimotor neuropathy and demyelinating

polyneuropathy

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 10

/l) was 8 days.

Neutrophil counts of < 0.5 x 10

/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

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

ases 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. Any suspected adverse events

should be reported to the Ministry of Health according to the National Regulation by using an online

form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.g

ov.il)

and e-mailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com

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

microtubule

dynamics

inhibitor

belonging

halichondrin

class

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 G

/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.

Study 305 - Updated Overall Survival ( ITT Population)

PROPORTION OF PATIENTS ALIVE

TIME (months)

NUMBER OF PATIENTS AT RISK

HALAVEN

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

Median (months)

13.2

10.5

Hazard Ratio (95% CI)

0.805 (0.677, 0.958)

Nominal P value

(log rank)

0.014

Cox proportional hazard

Stratified by geographic region, HER2/neu status,

and prior capecitabine therapy.

Treatment of

Physician’s Choice

(TPC)

HALAVEN

Study 301 - Overall Survival (ITT Population)

PROBABILITY OF SURVIVAL

TIME (months)

NUMBER OF PATIENTS AT RISK

HALAVEN

554 530 505 464 423 378 349 320 268 243 214 193 173 151 133 119

Capecitabine

548 513 466 426 391 352 308 277 242 214 191 175 155 135 122 108

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

Median months

13.4

10.5

11.8

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

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.

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

Efficacy Parameter

OS in ITT Population

HALAVEN

(n=554)

Capecitabine

(n=548)

Number of Events

Median (months)

15.9

14.5

Hazard Ratio (95% CI)

0.879 (0.770, 1.003)

P value (log rank)

0.056

Cox proportional hazard

Stratified by geographic region, HER2/neu status

Capecitabine

HALAVEN

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/m

on days 1 and 8 of a 21 day cycle or dacarbazine

850 mg/m

, 1000 mg/m

or 1200 mg/m

(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

Median

months

15.6

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

Median

months

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

Study 309 - Overall Survival in the Liposarcoma Subgroup

PROBABILITY OF SURVIVAL

Time (months)

NUMBER OF PATIENTS AT RISK:

HALAVEN

Dacarbazine

Study 309 – Progression Free Survival in the Liposarcoma Subgroup

PROBABILITY OF SURVIVAL

Time (months)

NUMBER OF PATIENTS AT RISK:

HALAVEN

Dacarbazine

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

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/m

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

C-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/m

). 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/m

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 C

). In vitro studies have also indicated that eribulin is not a substrate for

OCT1.

After administration of

C-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/m

patients with mild hepatic impairment and 0.62 mg/m

to patients with moderate hepatic impairment

resulted in a somewhat higher exposure than after a dose of 1.23 mg/m

to patients with normal hepatic

function. HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C). There

study

patients

with

hepatic

impairment

cirrhosis.

section

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), 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

(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

Dehydrated alcohol

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

The expiry date of the product is indicated on the packaging materials.

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

Store below 25ºC

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.

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.

MANUFACTURER

Eisai Manufacturing limited, UK.

8.

REGISTRATION HOLDER

Neopharm Scientific Ltd.

6 Hashiloach street

P.O.Box 7063

Petach Tiqva 49170.

9.

REGISTRATION NUMBER

148-18-33511

The content of this leaflet was approved by the Ministry of Health in Februar 2017 and updated

according to the guidelines of the Ministry of Health in June 2019.

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