Halaven 0.44 mg/ml solution for injection

Documented changes

Sections of the SmPC

Changes/updates

Section 4.4 Special warnings and precautions for use

 The following underlined information was added under ‘QT prolongation’:

Hypokalaemia, hypocalcaemia or hypomagnesaemia should be corrected prior to initiating HALAVEN and these electrolytes should be monitored periodically during therapy.

Section 4.8 Undesirable effects

 Hypocalcaemia was added as a common adverse reaction (≥ 1/100 to < 1/10), under ‘Metabolism and nutrition disorders’ in section 4.8

Section 7 Marketing Authorisation Holder

Marketing Authorisation Holder details have been updated:

Eisai GmbH

Lyoner Straße 36

60528 Frankfurt am Main

Germany

E-mail: medinfo_de@eisai.net

Section 10 Date of revision of the text

The date of revision of text has been updated to 01/2019

Documented Changes

Section of the SmPC

Changes / Updates

·         Section 4.8 (Undesirable effects)

The ‘Rare’ column of the adverse reactions table has changed to ‘Rare or not known’

The following adverse reactions have been added to the skin and subcutaneous tissue disorders column under ‘Rare or not Known’:

^{·          **Stevens-Johnson syndrome/ Toxic epidermal necrolysisb}

^b From spontaneous reporting

^** Frequency not known

·         Section 10 (Date of revision of text)

The Date of revision of text has been updated

Documented changes

Sections of the SPC

Changes/updates

Section 4.1

Section 4.1 has been updated with the new indication as follows: “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).”

Section 4.2

·        Removal of: “in units specialised in the administration of cytotoxic chemotherapy”

·        Addition of the following statement under Paediatric population: “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.”

Section 4.4

Addition of: “Fatal cases of febrile neutropenia, neutropenic sepsis, sepsis and septic shock have been reported.”

Section 4.5

·        Following section has been removed: “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) and 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, 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 Cmax) 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.” and replaced with:

“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_max) was unaffected by ketoconazole, a CYP3A4 and P glycoprotein (Pgp) inhibitor, and rifampicin, a CYP3A4 inducer.”

·        Section 4.5 has also been updated with the following text in the paragraph discussing the effects of eribulin on the pharmacokinetics of other medicines: “At relevant clinical concentrations, eribulin did not inhibit BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1 and OATP1B3 transporter-mediated activity.”

Section 4.8

Section 4.8 has been updated to include patients from Study 309 (phase 3 study).
• In light of the additional safety information, the table of adverse reactions has been updated in the SPC. New adverse reaction appears in the tabulated list: Septic Shock (0.2%) (G3/4:0.2%) - Uncommon - Includes Grade 5 events.

The following text has also been added to section 4.8:

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

Section 4.8 has been updated regarding neutropenia, peripheral neuropathy and elderly population as follows:

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.

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%.

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.

Section 5.1

·        Removal of the term “non-taxane” from the description of eribulin mesilate.

·        the addition of “irreversible” mitotic blockage

·         

Addition of liposarcoma efficacy data from the phase 3 study; Study 309.

• Addition of tabulated overall survival and progression-free survival subgroup data for liposarcoma and leimoyosarcoma patients and ITT population in study 309.

Addition of wording regarding paediatric soft tissue sarcoma population: “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.”

Section 10

The date of revision has been updated

Documented changes

Sections of the SPC

Changes/updates

Leaflet Header

Removal of the black triangle and following text: " This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions."

Section 4.4

Removal of the following statement:

"Use in combination with anti-HER2 therapy

The efficacy and safety of using eribulin in combination with anti-HER2 therapy have not been established."

Section 5.2

Correction to the numbers of patients in the renal impairment section. Updated text states:

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.

Section 10

 Date of revision of the text has been updated

Documented changes

Sections of the SPC

Changes/updates

section 4.1

 The addition of the word 'adult' to the indication.

Section 4.2

The addition of wording “HALAVEN is for intravenous use” under ‘Method of administration’ section.

Section 9

Date of latest renewal has been added: 19 November 2015

Section 10

Date of revision of the text

Throughout the SPC

Correction of spelling/typing errors

Documented changes

Sections of the SPC

Changes/updates

Section 4.4

Change of wording under the subheading ‘Use in combination with anti-HER2 therapy’ to the following: “The efficacy and safety of using eribulin in combination with anti-HER2 therapy have not been established.”

Section 6.6

Addition of the following warning statement: “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.”

Section 10

Date of revision of the text