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 a full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless aqueous solution.

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

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

Posology

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

Please note:

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

In the pivotal EMBRACE trial, the corresponding publication and in some other regions e.g. the US 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 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

Do not re-escalate the eribulin dose 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

Patients with severely impaired renal function (creatinine clearance <40 ml/min) may need a reduction of the dose (see section 5.2). The optimal dose for this patient groups remains to be established. Caution and close safety monitoring as advised. No specific dose adjustments are recommended for patients with mild to moderate renal impairment.

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 in the indication of breast cancer.

Method of administration

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 drugs see section 6.6.

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

- Breast feeding

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 breast cancer 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 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.

Severe neutropenia may be managed by the use of 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, medicinal products known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Hypokalemia or hypomagnesemia 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.

Use in combination with anti-HER2 therapy

There is no experience of using eribulin in combination with anti-HER2 therapy in clinical trials.

Excipients

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 in this process is unknown. Complete inhibition of the transport could in theory give rise to a more than 3-fold increase in plasma concentrations. It is not recommended to use substances which are inhibitors of hepatic transport proteins such as organic anion-transporting proteins (OATPs), P-glycoprotein (Pgp), multidrug resistant proteins (MRPs) etc concomitantly with eribulin. Inhibitors of such transporters include but are not limited to: cyclosporine, ritonavir, saquinavir, lopinavir and certain other protease inhibitors, efavirenz, emtricitabine, verapamil, clarithromycin, quinine, quinidine, disopyramide etc.

It cannot be excluded that concomitant treatment with inducing substances, such as carbamazepine, phenytoin, St John´s wort (Hypericum perforatum), could give rise to reduced plasma concentrations of eribulin, and co-administration with inducers should be carried out with caution considering a potential risk for reduced drug efficacy. No marked effects on eribulin exposure (AUC and C_max) were observed during treatment with the CYP3A4 inducer rifampicin. However, rifampicin may due to its transporter inhibitory property counteract its possible inducing effect on eribulin elimination. Therefore, the effect of rifampicin may not presently be extrapolated to other inducers.

No drug-drug interactions are expected with CYP3A4 inhibitors. Eribulin exposure (AUC and C_max) was unaffected by ketoconazole, a CYP3A4 inhibitor.

Effects of eribulin on the pharmacokinetics of other drugs

Eribulin may inhibit the important drug metabolising enzyme CYP3A4. This is indicated by in vitro data and no in vivo data is available.

Concomitant use with substances that are mainly metabolised by CYP3A4 should be made with caution and it is recommended that the patient is closely monitored for adverse effects due to increased plasma concentrations of the concomitantly used substance. If the substance has a narrow therapeutic range, concomitant use should be avoided.

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

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 breastfeeding (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.

HALAVEN may cause adverse reactions such as tiredness and dizziness which may lead to a 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.

Unless otherwise noted, the table shows the incidence rates of adverse reactions observed in 827 breast cancer patients who received the recommended dose in two Phase 2 and one Phase 3 study.

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 with a frequency of ≥ 1%, the actual total frequency and the frequency of Grade 3 or 4 reactions are given.

^a Includes 1 Grade 5

^b Includes preferred terms of peripheral neuropathy, peripheral motor neuropathy, polyneuropathy, paraesthesia, peripheral sensory neuropathy, peripheral sensorimotor neuropathy and demyelinating polyneuropathy

^c No Grade 4

^d From spontaneous reporting

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.

Severe neutropenia may be managed by the use of G-CSF or equivalent at the physician's discretion in accordance with relevant guidelines. 18% of breast cancer patients treated in a phase 3 study with eribulin 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 827 breast cancer patients the most common adverse reaction resulting in discontinuation of treatment with eribulin was peripheral neuropathy (4%). The median time to Grade 2 peripheral neuropathy was 85 days (post 4 cycles).

Development of Grade 3 or 4 peripheral neuropathy occurred in 7% of eribulin treated breast cancer 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 patients with pre-existing Grade 1 or 2 peripheral neuropathy the frequency of treatment-emergent Grade 3 peripheral neuropathy was 10%.

Special populations

Elderly population

In studies of 1,222 patients treated with eribulin, 244 patients (20.0%) were > 65 ‑ 75 years of age and 66 patients (5.4%) were > 75 years of age. Among the 827 of these patients who received the recommended dose of eribulin in the Phase 2/3 breast cancer studies, 121 patients (14.6%) were > 65 ‑ 75 years of age and 17 patients (2.1%) were > 75 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. No dose adjustments are recommended for the elderly population.

Patients with hepatic impairment

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

Reporting of suspected adverse reactions

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

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.

Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XX41

HALAVEN (eribulin mesilate) is a non-taxane, microtubule dynamics inhibitor belonging to the halichondrin class of antineoplastic agents. It is a structurally simplified synthetic analogue of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai.

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

Clinical efficacy

The efficacy of HALAVEN in breast cancer is supported by two single-arm Phase 2 studies and a randomized Phase 3 comparative study.

The 762 patients in the pivotal Phase 3 EMBRACE study 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. They were randomized 2:1 to receive either HALAVEN at a dose of 1.23 mg/m² on Days 1 and 8 in a 21‑day cycle administered intravenously over 2 to 5 minutes, or treatment of physician's choice (TPC), defined as any single-agent chemotherapy, hormonal treatment, or biologic therapy approved for the treatment of cancer; or palliative treatment or radiotherapy, reflecting local practice. The TPC arm 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 result that was statistically significantly better in the eribulin group compared to TPC at 55% of events. The median survival of the HALAVEN group (median: 399 days/13.1 months) compared with the TPC group (median: 324 days/10.6 months) improved by 75 days/2.5 months (HR 0.809, 95% CI: 0.660, 0.991, p=0.041).

This result was confirmed with an updated overall survival analysis carried out at 77% of events with the median survival of the HALAVEN group (median: 403 days/13.2 months) compared with the TPC group (median: 321 days/10.5 months) improved by 82 days/2.7 months (HR 0.805, 95% CI: 0.677, 0.958, nominal p=0.014).

Efficacy of HALAVEN versus Treatment of Physician's Choice – Updated Survival Analysis in the ITT Population

^a Stratified by geographic region, HER2/neu status, and prior capecitabine therapy.

Kaplan-Meier Analysis of OS-Update Data (ITT Population)

At the time of the original cut-off, analysis of progression free survival by independent and investigator review is shown in the following table.

Efficacy of HALAVEN versus Treatment of Physician's Choice – Progression Free Survival

In response evaluable patients who received HALAVEN, the objective response rate by the RECIST criteria was 12.2% (95% CI: 9.4%, 15.5%) by independent review and 13.2% (95% CI: 10.3%, 16.7%) by investigator review. The median response duration in this population by independent review was 128 days (95% CI: 116, 152 days) (4.2 months).

The positive effect on OS and PFS 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. In the Investigator assessment-based analysis of PFS (based on original data cut-off), the HR was 0.77 (95% CI 0.61, 0.97) for taxane-refractory patients and 0.76 (95% CI 0.58, 0.99) for patients not taxane-refractory.

The positive effect on OS was seen both in capecitabine-naïve and in capecitabine pre-treated patient groups. The analysis of updated OS 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). Investigator assessment-based analysis of PFS (based on original data cut-off), also showed a positive effect in the capecitabine pre-treated group with a HR of 0.68 (0.56, 0.83). For the capecitabine-naïve group the corresponding HR was 1.03 (0.73, 1.45).

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.

Distribution

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

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

Biotransformation

Unchanged eribulin was the major circulating species in plasma following administration of ¹⁴C-eribulin to patients. Metabolite concentrations represented <0.6% of parent compound, confirming that there are no major human metabolites of eribulin.

Elimination

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

Eribulin is eliminated primarily by biliary excretion. The transport protein involved in the excretion is presently unknown. Preclinical studies indicate that eribulin is transported by Pgp. However, it is unknown whether Pgp is contributing to the biliary excretion of eribulin.

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

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

Hepatic impairment

A study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=4) hepatic impairment due to liver metastases. Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 3-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 0.97 mg/m² to patients with mild hepatic impairment and 0.62 mg/m² to patients with moderate hepatic impairment resulted in a somewhat higher exposure than after a dose of 1.23 mg/m² to patients with normal hepatic function. HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C). There is no study in patients with hepatic impairment due to cirrhosis. See section 4.2 for dosage recommendation.

Renal impairment

A study in patients with different degrees of impaired renal function showed that the exposure of eribulin in patients with moderate renal function (creatinine clearance ≥ 40 to 59 ml/min, n=6) was similar to patients with normal renal function while the exposure in patients with severe impairment was increased by 75% (creatinine clearance < 40 ml/min, n=4). See section 4.2 for treatment recommendations.

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.

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 medicinal products except those mentioned in section 6.6.

Unopened vials

4 years.

In-use shelf life

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

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

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

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, 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. 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.

Eisai Europe Ltd

European Knowledge Centre

Mosquito Way

Hatfield

Hertfordshire

AL10 9SN

United Kingdom

EU/1/11/678/001-002

Date of first authorisation: 17 March 2011

April 2013

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