HALAVEN 0.44mg / ml solution for injection medication leaflet

HALAVEN 0.44 mg/ml solution for injection

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.

Solution for injection (injection).

Clear, colourless aqueous solution.

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

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

HALAVEN should only be prescribed by a qualified physician experienced in the appropriate use ofanti-cancer therapy. It should be administered by an appropriately qualified healthcare professionalonly.

The recommended dose of eribulin as the ready to use solution is 1.23 mg/m2 which should beadministered 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 ofthe individual dose to be administered to a patient must be based on the strength of the ready to usesolution that contains 0.44 mg/ml eribulin and the dose recommendation of 1.23 mg/m2. The dosereduction recommendations shown below are also shown as the dose of eribulin to be administeredbased 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 Statesand Switzerland, the recommended dose is based on the salt form (eribulin mesilate).

Patients may experience nausea or vomiting. Antiemetic prophylaxis including corticosteroids shouldbe 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 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 oferibulin

Haematological:

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

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 0.97 mg/m2haemorrhage or requiring blood or platelet transfusion

Non-haematological:

Any Grade 3 or 4 in the previous cycle

Reoccurrence of any haematological or non-haematologicaladverse 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.

Impaired liver function due to metastases

The recommended dose of eribulin in patients with mild hepatic impairment (Child-Pugh A) is0.97 mg/m2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. Therecommended dose of eribulin in patients with moderate hepatic impairment (Child-Pugh B) is0.62 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 markeddose 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 moderateimpairment but close monitoring is advised as the doses may need readjustment.

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 renalimpairment, caution and close safety monitoring is advised. (See section 5.2)

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

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

There is no relevant use of HALAVEN in the paediatric population for the indication of soft tissuesarcoma (see section 5.1).

HALAVEN is for intravenous use. The dose may be diluted in up to 100 ml of sodium chloride9 mg/ml (0.9%) solution for injection. It should not be diluted in glucose 5% infusion solution. Forinstructions on the dilution of the medicinal product before administration, see section 6.6. Goodperipheral venous access, or a patent central line, should be ensured prior to administration. There isno evidence that eribulin mesilate is a vesicant or an irritant. In the event of extravasation, treatmentshould be symptomatic. For information relevant to the handling of cytotoxic medicinal products seesection 6.6.

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

- Breast-feeding

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 oferibulin. Treatment with eribulin should only be initiated in patients with ANC values ≥ 1.5 x 109/l andplatelets > 100 x 109/l.

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

Patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 x upper limit ofnormal (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 4neutropenia 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) orequivalent at the physician’s discretion in accordance with relevant guidelines (see section 5.1).

Patients should be closely monitored for signs of peripheral motor and sensory neuropathy. Thedevelopment 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 worseningsymptoms than those who entered the study without the condition.

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 monitoringis recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias orconcomitant treatment with medicinal products known to prolong the QT interval, including Class Iaand III antiarrhythmics, and electrolyte abnormalities. Hypokalaemia, hypocalcaemia orhypomagnesaemia should be corrected prior to initiating HALAVEN and these electrolytes should bemonitored periodically during therapy. Eribulin should be avoided in patients with congenital long QTsyndrome.

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

Eribulin is mainly (up to 70%) eliminated through biliary excretion. The transport protein involved inthis process is unknown. Eribulin is not a substrate of breast cancer resistance protein (BCRP), organicanion (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, andrifampicin, 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 recommendedwith concomitant use of substances that have a narrow therapeutic window and that are eliminatedmainly via CYP3A4-mediated metabolism (e.g. alfentanil, cyclosporine, ergotamine, fentanyl,pimozide, quinidine, sirolimus, tacrolimus).

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

At relevant clinical concentrations, eribulin did not inhibit BCRP, OCT1, OCT2, OAT1, OAT3,

OATP1B1 and OATP1B3 transporter-mediated activity.

There are no data from the use of eribulin in pregnant women. Eribulin is embryotoxic, foetotoxic, andteratogenic in rats. HALAVEN should not be used during pregnancy unless clearly necessary and aftera 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 arereceiving HALAVEN and must use highly effective contraception during treatment with HALAVENand for 7 months after treatment.

Men with partners of child-bearing potential should be advised not to father a child while receiving

HALAVEN and must use effective contraception during HALAVEN treatment and for 4 months aftertreatment.

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

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

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

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

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

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 4reactions are given.

System Organ Adverse Reactions - all Grades

Class

Very Common Common Uncommon Rare or not(Frequency %) (Frequency %) (Frequency %) known

Infections and Urinary tract Sepsis (0.5%) (G3/4:infestations infection (8.5%) 0.5%)a(G3/4: 0.7%) Neutropenic sepsis

Pneumonia (1.6%) (0.2%) (G3/4: 0.2%)a(G3/4: 1.0%) Septic Shock (0.2%)

Oral candidiasis (G3/4:0.2%)a

Oral herpes

Upper respiratorytract infection

Nasopharyngitis

Rhinitis

Herpes zoster

Blood and Neutropenia (53.6%) Lymphopenia (5.7%) *Disseminatedlymphatic system (G3/4: 46.0%) (G3/4: 2.1%) intravasculardisorders Leukopenia (27.9%) Febrile neutropenia coagulationb(G3/4: 17.0%) (4.5%) (G3/4: 4.4%)a

Anaemia (21.8%) Thrombocytopenia(G3/4: 3.0%) (4.2%) (G3/4: 0.7%)

System Organ Adverse Reactions - all Grades

Class

Very Common Common Uncommon Rare or not(Frequency %) (Frequency %) (Frequency %) known

Metabolism and Decreased appetite Hypokalaemia (6.8%)nutrition (22.5%) (G3/4: 0.7%)d (G3/4: 2.0%)disorders Hypomagnesaemia(2.8%) (G3/4: 0.3%)

Dehydration (2.8 %)(G3/4: 0.5%)d

Hypophosphataemia

Psychiatric Insomniadisorders Depression

Nervous system Peripheral neuropathyc Dysgeusiadisorders (35.9%) (G3/4: 7.3%) Dizziness (9.0%)

Headache (17.5%) (G3/4: 0.4%)d(G3/4: 0.7%) Hypoaesthesia

Lethargy

Neurotoxicity

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

Conjunctivitis

Ear and labyrinth Vertigodisorders Tinnitus

Cardiac disorders Tachycardia

Vascular Hot flush Deep vein thrombosisdisorders Pulmonary embolism(1.3%) (G3/4: 1.1%)a

Respiratory, Dyspnoea (15.2%)a Oropharyngeal pain Interstitial lungthoracic and (G3/4: 3.5%)a Epistaxis disease (0.2%) (G3/4:mediastinal Cough (15.0%) (G3/4: Rhinorrhoea 0.1%)disorders 0.5%)d

Gastrointestinal Nausea (35.7%) (G3/4: Abdominal pain Mouth ulcerationdisorders 1.1%)d Stomatitis (11.1%) Pancreatitis

Constipation (22.3%) (G3/4: 1.0%)d(G3/4: 0.7%)d Dry mouth

Diarrhoea (18.7%) Dyspepsia (6.5%)(G3/4: 0.8%) (G3/4: 0.3%)d

Vomiting (18.1%) Gastrooesophageal(G3/4: 1.0%) reflux disease

Abdominal distension

Hepatobiliary Aspartate Hepatotoxicitydisorders aminotransferase (0.8%) (G3/4: 0.6%)increased (7.7%)(G3/4: 1.4%)d

Alanineaminotransferaseincreased (7.6%)(G3/4: 1.9%)d

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

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

System Organ Adverse Reactions - all Grades

Class

Very Common Common Uncommon Rare or not(Frequency %) (Frequency %) (Frequency %) known

Skin and Alopecia Rash (4.9%) (G3/4: Angioedema **Stevens-Johnsonsubcutaneous 0.1%) syndrome/ Toxictissue disorders Pruritus (3.9%) epidermal(G3/4: 0.1%)d necrolysisb

Nail disorder

Night sweats

Dry skin

Erythema

Hyperhidrosis

Palmar plantarerythrodysaesthesia(1.0%) (G3/4: 0.1%)d

Musculoskeletal Arthralgia and myalgia Bone pain (6.7%)and connective (20.4%) (G3/4: 1.0%) (G3/4: 1.2%)tissue disorders Back pain (12.8%) Muscle spasms(G3/4: 1.5%) (5.3%) (G3/4: 0.1%)d

Pain in extremity Musculoskeletal pain(10.0%) (G3/4: 0.7%)d Musculoskeletalchest pain

Muscular weakness

Renal and urinary Dysuria Haematuriadisorders Proteinuria

General disorders Fatigue/Asthenia Mucosaland (53.2%) (G3/4: 7.7%) Inflammation (6.4%)administration site Pyrexia (21.8%) (G3/4: 0.9%)dconditions (G3/4: 0.7%) Peripheral oedema

Chills

Chest pain

Influenza like illness

Investigations Weight decreased(11.4%) (G3/4: 0.4%)da Includes Grade 5 events.b From spontaneous reportingc Includes preferred terms of peripheral neuropathy, peripheral motor neuropathy, polyneuropathy,paraesthesia, peripheral sensory neuropathy, peripheral sensorimotor neuropathy and demyelinatingpolyneuropathyd No Grade 4 events

* Rare

** Frequency not known

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

The neutropenia observed was reversible and not cumulative; the mean time to nadir was 13 days andthe 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 cancerpatients treated with eribulin in the EMBRACE study.

Neutropenia was reported as a Treatment Emergent Adverse Event (TEAE) in 151/404 (37.4% for allgrades) in the sarcoma population, compared with 902/1559 (57.9% for all grades) in the breast cancerpopulation. The combined grouped TEAE and neutrophil laboratory abnormality frequencies were307/404 (76.0%) and 1314/1559 (84.3%), respectively. The median duration of treatment was 12.0weeks 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. Outof 1963 breast cancer and soft tissue sarcoma patients who received eribulin at the recommended dosein 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 inaccordance with relevant guidelines. 18% and 13% of eribulin treated patients received G-CSF in thetwo 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 withneutropenia and/or sepsis.

In the 1559 breast cancer patients the most common adverse reaction resulting in discontinuation oftreatment with eribulin was peripheral neuropathy (3.4%). The median time to Grade 2 peripheralneuropathy was 12.6 weeks (post 4 cycles). Out of the 404 sarcoma patients, 2 patients discontinuedtreatment with eribulin due to peripheral neuropathy. The median time to Grade 2 peripheralneuropathy was 18.4 weeks.

Development of Grade 3 or 4 peripheral neuropathy occurred in 7.4% of breast cancer patients and3.5% of sarcoma patients. In clinical trials, patients with pre-existing neuropathy were as likely todevelop 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 oftreatment-emergent Grade 3 peripheral neuropathy was 14%.

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

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%) treatedwith eribulin were ≥ 65 years of age. The safety profile of eribulin in elderly patients (≥ 65 years ofage) was similar to that of patients <65 years of age except for asthenia/fatigue which showed anincreasing trend with age. No dose adjustments are recommended for the elderly population.

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

Three open-label studies, Studies 113, 213 and 223, were conducted in paediatric patients withrefractory or recurrent solid tumours and lymphomas, but excluding central nervous system (CNS)tumours (see section 5.1).

The safety of eribulin monotherapy was evaluated in 43 paediatric patients who received up to1.58 mg/m2 on Days 1 and 8 of a 21-day cycle (Studies 113 and 223). The safety of eribulin incombination with irinotecan was also evaluated in 40 paediatric patients who received eribulin1.23 mg/m2 on Days 1 and 8 and irinotecan 20 or 40 mg/m2 on Days 1 to 5 of a 21-day cycle, or 100 or125 mg/m2 on Days 1 and 8 of a 21-day cycle (Study 213).

In Study 113 (Phase 1), the most frequently reported adverse drug reactions were white blood cellcount decreased, lymphocyte count decreased, anaemia and neutrophil count decreased.

In Study 213 (Phase 1/2), the most frequently reported adverse drug reactions were neutropenia(Phase 1) and diarrhoea and neutrophil count decreased (Phase 2).

In Study 223 (Phase 2), the most frequently reported adverse drug reactions were neutrophil countdecreased, anaemia, and white blood cell count decreased.

The safety profile of eribulin as monotherapy or in combination with irinotecan hydrochloride in thispaediatric population was consistent with the known safety profile of either study drug in the adultpopulation.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In one case of overdose the patient inadvertently received 7.6 mg of eribulin (approximately 4 timesthe planned dose) and subsequently developed a hypersensitivity reaction (Grade 3) on Day 3 andneutropenia (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 beclosely monitored. Management of overdose should include supportive medical interventions to treatthe presenting clinical manifestations.

Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX41

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

Eribulin inhibits the growth phase of microtubules without affecting the shortening phase andsequesters tubulin into non-productive aggregates. Eribulin exerts its effects via a tubulin-basedantimitotic mechanism leading to G2/M cell-cycle block, disruption of mitotic spindles, and,ultimately, apoptotic cell death after prolonged and irreversible mitotic blockage.

Breast cancer

The efficacy of HALAVEN in breast cancer is primarily supported by two randomized Phase 3comparative studies.

The 762 patients in the pivotal Phase 3 EMBRACE study (Study 305) had locally recurrent ormetastatic breast cancer, and had previously received at least two and a maximum of fivechemotherapy regimens, including an anthracycline and a taxane (unless contraindicated). Patientsmust have progressed within 6 months of their last chemotherapeutic regimen. The HER2 status of thepatients was: 16.1% positive, 74.2% negative and 9.7% unknown, whilst 18.9% of patients were triplenegative. 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 statisticallysignificantly 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)

Efficacy Parameter HALAVEN TPC1.0 HALAVEN (n=508) (n=254)0.9 Overall Survival0.8 Number of Events 386 2030.7 Median (months) 13.2 10.5

Treatment of0.6 Physician’s Choice Hazard Ratio (95% CI)a 0.805 (0.677, 0.958)(TPC)0.5 Nominal P value 0.014b(log rank)0.4 aCox proportional hazardbStratified by geographic region, HER2/neu status,0.3 and prior capecitabine therapy.

0.20.10.0

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 eribulincompared to 2.2 months for the TPC arm (HR 0.865, 95% CI: 0.714, 1.048, p=0.137). In responseevaluable 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. Inthe OS update, the HR for eribulin versus TPC was 0.90 (95% CI: 0.71, 1.14) in favour of eribulin fortaxane-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 patientgroups. The updated OS analysis showed a survival benefit for the eribulin group compared to TPCboth in capecitabine pre-treated patients with a HR of 0.787 (95% CI: 0.645, 0.961), and for thecapecitabine-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 toinvestigate the efficacy of HALAVEN monotherapy compared to capecitabine monotherapy in termsof OS and PFS as co-primary endpoint. Patients had previously received up to three priorchemotherapy regimens, including both an anthracycline and a taxane and a maximum of two foradvanced disease, with the percentage who had received 0, 1 or 2 prior chemotherapy treatments formetastatic breast cancer being 20.0%, 52.0% or 27.2% respectively. The HER2 status of the patients

PROPORTION OF PATIENTS ALIVEwas: 15.3% positive, 68.5% negative and 16.2% unknown, whilst 25.8% of patients were triplenegative.

Study 301 - Overall Survival (ITT Population)

Efficacy Parameter OS in ITT Population1.0

HALAVEN Capecitabine0.9 HALAVEN (n=554) (n=548)0.8 Number of Events 446 4590.7 Median (months) 15.9 14.5

Capecitabine a0.6 Hazard Ratio (95% CI) 0.879 (0.770, 1.003)0.5 P value (log rank) 0.056baCox proportional hazard0.4 bStratified by geographic region, HER2/neu status0.30.20.10.0

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 andcapecitabine 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 betweeneribulin 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 andcontrol groups in Study 305 and Study 301 is shown below:

Efficacy Parameter Study 305 Updated Overall Survival ITT Population

HER2 Negative HER2 Positive

HALAVEN TPC HALAVEN TPC(n = 373) (n = 192) (n = 83) (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 Capecitabine HALAVEN Capecitabine(n = 375) (n = 380) (n = 86) (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.

PROBABILITY OF SURVIVAL

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 tissuesarcoma of one of two subtypes - leiomyosarcoma or liposarcoma. Patients had received at least twoprior 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 wererandomized 1:1 to receive either eribulin 1.23 mg/m2 on days 1 and 8 of a 21 day cycle or dacarbazine850 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 theeribulin 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 wasno significant difference in progression-free survival or overall response rate between the treatmentarms 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 OSand PFS. There was no difference in efficacy between eribulin and dacarbazine in patients withadvanced or metastatic leiomyosarcoma.

Study 309 Study 309 Study 309

Liposarcoma Subgroup Leiomyosarcoma Subgroup ITT Population

HALAVEN Dacarbazine HALAVEN Dacarbazine HALAVEN Dacarbazine(n=71) (n=72) (n=157) (n=152) (n=228) (n=224)

Overall survival

Number of

Events 52 63 124 118 176 181

Medianmonths 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)

Nominalp-value 0.0006 0.5730 0.0169

Progression-free survival

Number of

Events 57 59 140 129 197 188

Medianmonths 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)

Nominalp-value 0.0015 0.5848 0.2287

Study 309 - Overall Survival in the Liposarcoma Subgroup

HALAVEN

Dacarbazine

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

HALAVEN

Dacarbazine

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

PROBABILITY OF SURVIVAL

PROBABILITY OF SURVIVAL

Breast Cancer

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

Soft Tissue Sarcoma

Efficacy of eribulin was assessed but not established in three open-label studies:

Study 113 was a Phase 1, open-label, multicentre, dose-finding study that assessed eribulin inpaediatric patients with refractory or recurrent solid tumours and lymphomas but excluding CNStumours. A total of 22 paediatric patients (age range: 3 to 17 years) were enrolled and treated. Thepatients were administered eribulin intravenously on Days 1 and 8 of a 21-day cycle at three doselevels (0.97, 1.23 and 1.58 mg/m2). The maximum tolerated dose (MTD)/recommended Phase 2 dose(RP2D) of eribulin was determined as 1.23 mg/m2 on Days 1 and 8 of a 21-day cycle.

Study 223 was a Phase 2, open-label, multicentre study that assessed the safety and preliminaryactivity of eribulin in paediatric patients with refractory or recurrent rhabdomyosarcoma (RMS),non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) or Ewing sarcoma (EWS). Twenty-onepaediatric patients (age range: 2 to 17 years) were enrolled and treated with eribulin at a dose of1.23 mg/m2 intravenously on Days 1 and 8 of a 21-day cycle (the RP2D from Study 113). No patientachieved confirmed partial response (PR) or complete response (CR).

Study 213 was a Phase 1/2, open-label, multicentre study to evaluate the safety and efficacy of eribulinin combination with irinotecan hydrochloride in paediatric patients with relapsed/refractory solidtumours and lymphomas but excluding CNS tumours (Phase 1), and to assess the efficacy of thecombination treatment in paediatric patients with relapsed/refractory RMS, NRSTS and EWS(Phase 2). A total of 40 paediatric patients were enrolled and treated in this study. In Phase 1,13 paediatric patients (age range: 4 to 17 years) were enrolled and treated; the RP2D was determinedas eribulin 1.23 mg/m2 on Days 1 and 8 with irinotecan hydrochloride 40 mg/m2 on Days 1 to 5 of a21-day cycle. In Phase 2, 27 paediatric patients (age range: 4 to 17 years) were enrolled and treated atthe RP2D. Three patients had confirmed PR (1 patient in each of the RMS, NRSTS, and EWShistology cohorts). The objective response rate (ORR) was 11.1%.

No new safety signals were observed in the three paediatric studies (see section 4.8); however, due tothe small patient populations no firm conclusions can be made.

The pharmacokinetics of eribulin are characterized by a rapid distribution phase followed by aprolonged elimination phase, with a mean terminal half-life of approximately 40 h. It has a largevolume 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.

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 thatthere are no major human metabolites of eribulin.

Eribulin has a low clearance (range of means 1.16 to 2.42 l/h/m2). No significant accumulation oferibulin is observed on weekly administration. The pharmacokinetic properties are not dose or timedependent 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 ispresently unknown. Preclinical in vitro studies indicate that eribulin is transported by Pgp. However ithas 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 oneribulin exposure (AUC and Cmax). In vitro studies have also indicated that eribulin is not a substratefor OCT1.

After administration of 14C-eribulin to patients, approximately 82% of the dose was eliminated infaeces 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.

A study evaluated the pharmacokinetics of eribulin in patients with mild (Child-Pugh A; n=7) andmoderate (Child-Pugh B; n=4) hepatic impairment due to liver metastases. Compared to patients withnormal hepatic function (n=6), eribulin exposure increased 1.8-fold and 3-fold in patients with mildand moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 0.97 mg/m2to patients with mild hepatic impairment and 0.62 mg/m2 to patients with moderate hepatic impairmentresulted in a somewhat higher exposure than after a dose of 1.23 mg/m2 to patients with normalhepatic 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 dosagerecommendation.

Increased eribulin exposure was seen in some patients with moderately or severely impaired renalfunction, 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 clearancewas 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 fortreatment recommendations.

Eribulin plasma concentrations were collected from 83 paediatric patients (age range: 2 to 17 years),with refractory/relapsed and recurrent solid tumours and lymphomas, who received eribulin in Studies113, 213 and 223. Eribulin PK in paediatric patients was comparable to adult patients with STS andpatients with other types of tumour. Eribulin exposure in paediatric patients was similar to exposure inadult patients. Concomitant irinotecan did not have an effect on eribulin PK in paediatric patients withrefractory/relapsed and recurrent solid tumours.

Eribulin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test). Eribulin waspositive in the mouse lymphoma mutagenesis assay and was clastogenic in the in vivo ratmicronucleus 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-dosestudies where testicular toxicity was observed in both rats (hypocellularity of seminiferous epitheliumwith hypospermia/aspermia) and dogs, male fertility may be compromised by treatment with eribulin.

An embryofoetal development study in rat confirmed the developmental toxicity and teratogenicpotential 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 ofresorptions and decreased foetal weight were observed at doses ≥ 0.088 mg/kg and increased incidenceof malformations (absence of lower jaw, tongue, stomach and spleen) was recorded at 0.133 mg/kg.

Ethanol anhydrous

Water for injections

Hydrochloric acid (for pH-adjustment)

Sodium hydroxide (for pH-adjustment)

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

Unopened vials5 years.

In-use shelf life

From a microbiological point of view the product should be used immediately. If not usedimmediately, in-use storage times and conditions are the responsibility of the user and would normallynot be longer than 24 hours at 2°C - 8°C, unless dilution has taken place in controlled and validatedaseptic conditions.

Chemical and physical in-use stability of HALAVEN as an undiluted solution in a syringe has beendemonstrated for up to 4 hours at 15-25°C and ambient lighting or up to 24 hours at 2°C - 8°C.

Chemical and physical in-use stability of HALAVEN as a diluted solution (0.018 mg/mL to 0.18mg/mL eribulin in sodium chloride 9 mg/mL (0.9%) has been demonstrated for up to 72 hours at2°C - 8°C.

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.

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.

HALAVEN is a cytotoxic anticancer medicinal product and, as with other toxic compounds, cautionshould be exercised in its handling. The use of gloves, goggles, and protective clothing isrecommended. If the skin comes into contact with the solution it should be washed immediately andthoroughly with soap and water. If it contacts mucous membranes, the membranes should be flushedthoroughly with water. HALAVEN should only be prepared and administered by personnelappropriately 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 flushedwith sodium chloride 9 mg/ml (0.9%) solution for injection to ensure administration of the completedose. It must not be mixed with other medicinal products and should not be diluted in glucose 5%infusion solution.

If using a spike to administer the product refer to the instructions provided from the devicemanufacturer. HALAVEN vials have a 13mm stopper. The device selected should be compatible withsmall vial stoppers.

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

Eisai GmbH

Edmund-Rumpler-Straße 360549 Frankfurt am Main

Germanye-mail: medinfo_de@eisai.net

EU/1/11/678/001-002

Date of first authorisation: 17 March 2011

Date of latest renewal: 19 November 2015

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.