Halaven 0.44 mg/ml solution for injection

  • Name:

    Halaven 0.44 mg/ml solution for injection

  • Company:
    info
  • Active Ingredients:

    Eribulin mesylate

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 08/03/19

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XPIL

Summary of Product Characteristics last updated on medicines.ie: 8/3/2019

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Eisai Ltd

Eisai Ltd

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1 - 0 of 12 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 8 March 2019 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - manufacturer
  • Change to section 6 - date of revision

Updated on 8 March 2019 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 1 August 2018 PIL

Reasons for updating

  • Change to section 6 - manufacturer
  • Change to section 6 - date of revision

Updated on 24 November 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 24 November 2017 PIL

Reasons for updating

  • Change to section 6 - date of revision
  • Change to MA holder contact details

Updated on 23 August 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 23 August 2017 SmPC

Reasons for updating

  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

 

Documented changes

Sections of the SmPC

Changes/updates

Section 6.3 Shelf life

Shelf life has changed from :

 

Unopened vials

4 years.

 

 

to:

 

Unopened vials

 

5 years

Section 10

 Revision date: 08/2017

 

Updated on 22 August 2016 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

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

Updated on 19 August 2016 PIL

Reasons for updating

  • Change to side-effects
  • Change to date of revision

Updated on 10 May 2016 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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 Cmax) 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

Updated on 5 May 2016 PIL

Reasons for updating

  • Change to, or new use for medicine
  • Change of contraindications
  • Change to side-effects
  • Change to date of revision
  • Changes to therapeutic indications

Updated on 30 March 2016 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
  • Removal of black triangle

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company



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

Updated on 29 March 2016 PIL

Reasons for updating

  • Change to date of revision
  • Change of distributor details
  • Removal of black triangle

Updated on 26 November 2015 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors
  • Change to improve clarity and readability

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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

Updated on 25 November 2015 PIL

Reasons for updating

  • Change to side-effects
  • Change to how the medicine works
  • Change to date of revision
  • Change to improve clarity and readability

Updated on 29 July 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.2, information on patients with renal impairment, has been updated:

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)

Section 5.2, data on renal impairment, has been updated:

Renal impairment

Increased eribulin exposure was seen in some patients with moderately or severely impaired renal function, with high between-subject variability. The pharmacokinetics of eribulin were evaluated in a Phase 1 study in patients with normal renal function (Creatinine clearance: ≥ 80 ml/min; n=7), moderate (30-50 ml/min; n=6) or severe (15-<30 ml/min; n=6) renal impairment. Creatinine clearance was estimated with the Cockcroft-Gault formula. A 1.5-fold (90% CI: 0.9-2.5) higher dose-normalised AUC(0-inf) was observed in patients with moderate and severe renal impairment. See section 4.2 for treatment recommendations.

Section 10 (date of the revision of the text) has been updated.

Updated on 3 June 2015 SmPC

Reasons for updating

  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company



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

Updated on 28 May 2015 PIL

Reasons for updating

  • Change to date of revision
  • Change to dosage and administration

Updated on 8 July 2014 SmPC

Reasons for updating

  • Correction of spelling/typing errors

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

There has been a small correction to the graph in section 5.1 for Study 301. The table has been updated to change 'TPC' to 'Capecitabine'.

Updated on 3 July 2014 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

The SPC has been updated following the EU Commission Decision for the indication extension for Halaven (eribulin).

Section 4.1 has been updated with the new indication as follows:

HALAVEN is indicated for the treatment of 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.

Section 4.4 has had some slight re-wording in the paragraph discussing QT prolongation. The following sentence was updated as follows (changes underlined):

• 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.

Section 4.5 has been updated with the following text in the paragraph discussing the effects of eribulin on the pharmacokinetics of other drugs:

• 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 effects is recommended with concomitant use of substances that have a narrow therapeutic window and that are eliminated mainly via CYP3A4-mediated metabolism (e.g. alfentanil, cyclosporine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus).

Section 4.8 has been updated with the addition of the following paragraph:

• Summary of safety profile

The most commonly reported undesirable effects related to HALAVEN, are bone marrow suppression manifested as neutropenia, leucopenia, anaemia, thrombocytopenia with associated infections. New onset or worsening of pre-existing peripheral neuopathy 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.

Section 4.8 has also been updated to include patients from three additional phase 2 studies and Study 301. The pooled safety population (referred to as the Breast Cancer Population [BCP]) now includes 1503 metastatic/advanced breast cancer patients who received the recommended dose of Halaven in a total of five (previously two) Phase 2 studies and two (previously one) Phase 3 studies.

• In light of the additional safety information, the table of adverse reactions has been updated in the SmPC.

The following text regarding hepatotoxicity has also been added to section 4.8:

• Hepatoxicity

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.

The special populations section regarding elderly patients was updated in section 4.8 to state that the safety profile in elderly patients >65 years was similar to that of patients ≤65 years, except for asthenia/fatigue, which showed an increasing trend with age.

Section 5.1 has been updated as follows:

• Results from the updated overall survival analysis from the phase 3 EMBRACE study (Study 305) at 77% events have been presented as a Kaplan-Meier plot, replacing the overall survival Kaplan-Meier plot at 55% events.

• Addition of efficacy data from the other phase 3 study; Study 301.

• Addition of tabulated overall survival subgroup data for patients with HER2-negative and HER2-positive metastatic breast cancer in studies 305 and 301.

Section 10; the date of revision of the text, has been updated to June 2014.

Updated on 2 July 2014 PIL

Reasons for updating

  • Change to, or new use for medicine
  • Change to side-effects
  • Change to date of revision

Updated on 11 March 2014 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.2 (Posology and method of administration) has been updated for patients with mild to moderate renal impairment, with the addition of 'close safety monitoring is advised'.

Section 4.5 (Interaction with other medicinal products and other forms of interaction) has been updated regarding transporters and enzyme inhibitors.

Section 5.2 (Pharmacokinetic properties) has been updated in the paragragraphs discussing elimination and renal impairment (changes underlined below):

Elimination

Eribulin is eliminated primarily by biliary excretion. The transport protein involved in the excretion is presently unknown. Preclinical in vitro studies indicate that eribulin is transported by Pgp. However it has been shown that at clinically relevant concentrations eribulin is not a Pgp inhibitor in vitro. Additionally, in vivo, concomitant administration of ketoconazole, a Pgp inhibitor, has no effect on eribulin exposure (AUC and Cmax). In vitro studies have also indicated that eribulin is not a substrate for OCT1.



Renal impairment

Data in patients with different degrees of impaired renal function showed that the exposure of eribulin in patients with mild to moderate renal impairment (creatinine clearance ≥ 40 to 80 ml/min) was increased in some patients, as compared to patients with normal renal function. The mean exposure in patients with severe impairment was increased by 75% (creatinine clearance < 40 ml/min, n=4). See section 4.2 for treatment recommendations.


Updated on 20 December 2013 PIL

Reasons for updating

  • New PIL for medicines.ie

Updated on 19 December 2013 SmPC

Reasons for updating

  • New SPC for medicines.ie

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

None provided