4.1. Therapeutic indications

Eribulin Eisai 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.

Eribulin Eisai 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

Eribulin Eisai should only be prescribed by a qualified physician experienced in the appropriate use of anti-cancer therapy. It should be administered by an appropriately qualified healthcare professional only.

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.

Dose delays during therapy

The administration of eribulin 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 eribulin 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 eribulin in children and adolescents for the indication of breast cancer.

There is no relevant use of eribulin in the paediatric population for the indication of soft tissue sarcoma (see section 5.1).

Method of administration

Eribulin Eisai 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 hypomagnesaemia should be corrected prior to initiating eribulin 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. Eribulin 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 are receiving eribulin and must use highly effective contraception during treatment with eribulin and for 7 months after treatment.

Men with partners of child-bearing potential should be advised not to father a child while receiving eribulin and must use effective contraception during eribulin treatment and for 4 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 eribulin 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 eribulin.

4.7. Effects on ability to drive and use machines

Eribulin 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 eribulin, 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

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%)dDiarrhoea (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%)

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 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).

Paediatric population

Three open-label studies, Studies 113, 213 and 223, were conducted in paediatric patients with refractory 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 to 1.58 mg/m2 on Days 1 and 8 of a 21-day cycle (Studies 113 and 223). The safety of eribulin in combination with irinotecan was also evaluated in 40 paediatric patients who received eribulin 1.23 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 or 125 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 cell count 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 count decreased, anaemia, and white blood cell count decreased.

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

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play and Apple App store.

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.