- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the 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.
PosologyThe 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 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 therapyThe 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 therapyDose reduction recommendations for retreatment are shown in the following table.
Dose reduction recommendations
|Adverse reaction after previous HALAVEN administration||Recommended dose of eribulin|
|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|
|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|
Patients with hepatic impairment
Impaired liver function due to metastasesThe 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 cirrhosisThis 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 impairmentSome 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 patientsNo specific dose adjustments are recommended based on the age of the patient (see section 4.8).
Paediatric populationThere is no relevant use of HALAVEN in children and adolescents for the indication of breast cancer.
Method of administrationHALAVEN 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.
HaematologyMyelosuppression 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 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. 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 neuropathyPatients 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 prolongationIn 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. 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 therapyThe efficacy and safety of using eribulin in combination with anti-HER2 therapy have not been established.ExcipientsThis medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per dose.
Effects of eribulin on the pharmacokinetics of other drugsIn 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.
PregnancyThere 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-feedingIt 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 breast-feeding (see section 4.3).
FertilityTesticular 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.
Summary of safety profileThe most commonly reported adverse reactions related to HALAVEN, 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 reactionsUnless otherwise noted, the table shows the incidence rates of adverse reactions observed in 1503 breast cancer patients who received the recommended dose in five Phase 2 and two 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|
|Infections and infestations||Urinary tract infection (8.0%) (G3/4: 0.5%) Pneumonia (1.2%) (G3/4: 0.8%) Oral candidiasis Oral herpes Upper respiratory tract infection Nasopharyngitis Rhinitis||Sepsis (0.5%) (G3/4: 0.2%)aNeutropenic sepsis (0.1%) (G3/4: 0.1%) Herpes zoster|
|Blood and lymphatic system disorders||Neutropenia (57.0%) (G3/4: 49.7%) Leukopenia (29.3%) (G3/4: 17.3%) Anaemia (20.6%) (G3/4: 2.0%)||Lymphopenia (4.9%) (G3/4: 1.4%) Febrile neutropenia (4.7%) (G3/4: 4.5%)a Thrombocytopenia (4.3%) (G3/4: 0.7%)||Disseminated intravascular coagulationb|
|Metabolism and nutrition disorders||Decreased appetite (21.9%) (G3/4: 0.7%)||Hypokalaemia (6.1%) (G3/4: 1.7%) Hypomagnesaemia (2.9%) (G3/4: 0.2%) Dehydration (2.8 %) (G3/4: 0.5%) Hyperglycaemia Hypophosphataemia|
|Psychiatric disorders||Insomnia Depression|
|Nervous system disorders||Peripheral neuropathyc (35.6%) (G3/4: 7.6%) Headache (17.2%) (G3/4: 0.8%)||Dysgeusia Dizziness (7.9%) (G3/4: 0.5%) Hypoaesthesia Lethargy Neurotoxicity|
|Eye disorders||Lacrimation increased (6.0%) (G3/4: 0.1%) Conjunctivitis|
|Ear and labyrinth disorders||Vertigo||Tinnitus|
|Vascular disorders||Hot flush||Deep vein thrombosis Pulmonary embolism|
|Respiratory, thoracic and mediastinal disorders||Dyspnoea (13.9%)a (G3/4: 3.1%) Cough (13.6%) (G3/4: 0.6%)||Oropharyngeal pain Epistaxis Rhinorrhoea||Interstitial lung disease|
|Gastrointestinal disorders||Nausea (33.8%) (G3/4: 1.1%) Constipation (19.6%) (G3/4: 0.6%) Diarrhoea (17.9%) (G3/4: 0.8%) Vomiting (17.6%) (G3/4: 0.9%)||Abdominal pain Stomatitis (9.3%) (G3/4: 0.8%) Dry mouth Dyspepsia (5.9%) (G3/4: 0.2%) Gastrooesophageal reflux disease Mouth ulceration Abdominal distension||Pancreatitisb|
|Hepatobiliary disorders||Alanine aminotransferase increased (7.6%) (G3/4: 2.1%)d Aspartate aminotransferase increased (7.4%) (G3/4: 1.5%) Gamma glutamyl transferase increased (1.8%) (G3/4: 0.9%) Hyperbilirubinaemia (1.5%) (G3/4: 0.3%)||Hepatotoxicity (1.0%) (G3/4: 0.6%)|
|Skin and subcutaneous tissue disorders||Alopecia||Rash Pruritus (3.9%) (G3/4: 0.1%) Nail disorder Night sweats Dry skin Erythema Hyperhidrosis||Palmar plantar erythrodysaesthesia||Angioedema|
|Musculoskeletal and connective tissue disorders||Arthralgia and myalgia (19.4%) (G3/4: 1.1%) Back pain (13.0%) (G3/4:1.5%) Pain in extremity (10.0%) (G3/4: 0.7%)||Bone pain ( 9.6%) (G3/4: 1.7%) Muscle spasms (5.1%) (G3/4: 0.1%) Musculoskeletal pain and musculoskeletal chest pain Muscular weakness|
|Renal and urinary disorders||Dysuria||Haematuria Proteinuria Renal failure|
|General disorders and administration site conditions||Fatigue/Asthenia (47.9%) (G3/4 : 7.8%) Pyrexia (20.4%) (G3/4: 0.6%)||Mucosal Inflammation (8.3%) (G3/4: 1.1%)d Peripheral oedema Pain Chills Chest pain Influenza like illness|
|Investigations||Weight decreased (11.3%) (G3/4: 0.3%)|
Description of selected adverse reactions
NeutropeniaThe 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.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 coagulationCases of disseminated intravascular coagulation have been reported, typically in association with neutropenia and/or sepsis.
Peripheral neuropathyIn the 1503 breast cancer patients the most common adverse reaction resulting in discontinuation of treatment with eribulin was peripheral neuropathy ( 3.3%). The median time to Grade 2 peripheral neuropathy was 85.5 days (post 4 cycles). Development of Grade 3 or 4 peripheral neuropathy occurred in 7.7% 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 14%.
HepatotoxicityIn 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.
Elderly populationOf the 1503 breast cancer patients treated with the recommended dose of eribulin, 209 patients (13.9%) were > 65 - 75 years of age and 24 patients (1.6%) 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 except for asthenia/fatigue which showed an increasing trend with age. No dose adjustments are recommended for the elderly population.
Patients with hepatic impairmentPatients 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 reactionsReporting 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 Website: www.mhra.gov.uk/yellowcard
Clinical efficacyThe efficacy of HALAVEN in breast cancer is primarily supported by two randomized Phase 3 comparative studies. The 762 patients in the pivotal Phase 3 EMBRACE study (Study 305) 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. The HER2 status of the patients was: 16.1% positive, 74.2% negative and 9.7% unknown, whilst 18.9% of patients were triple negative. 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 statistically significantly 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)By independent review, the median progression free survival (PFS) was 3.7 months for eribulin compared to 2.2 months for the TPC arm (HR 0.865, 95% CI: 0.714, 1.048, p=0.137). In response evaluable 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 . 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. The positive effect on OS was seen both in capecitabine-naïve and in capecitabine pre-treated patient groups. The updated OS analysis 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). 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 to investigate the efficacy of HALAVEN monotherapy compared to capecitabine monotherapy in terms of OS and PFS as co-primary endpoint. Patients had previously received up to three prior chemotherapy regimens, including both an anthracycline and a taxane and a maximum of two for advanced disease, with the percentage who had received 0, 1 or 2 prior chemotherapy treatments for metastatic breast cancer being 20.0%, 52.0% or 27.2% respectively. The HER2 status of the patients was: 15.3% positive, 68.5% negative and 16.2% unknown, whilst 25.8% of patients were triple negative.
Study 301 - Overall Survival (ITT Population)Progression free survival assessed by independent review was similar between eribulin and capecitabine 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 between eribulin 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 and control groups in Study 305 and Study 301 is shown below:
|Efficacy Parameter||Study 305 Updated Overall Survival ITT Population|
|HER2 Negative||HER2 Positive|
|HALAVEN(n = 373)||TPC(n = 192)||HALAVEN(n = 83)||TPC(n = 40)|
|Number of Events||285||151||66||37|
|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(n = 375)||Capecitabine(n = 380)||HALAVEN(n = 86)||Capecitabine(n = 83)|
|Number of Events||296||316||73||73|
|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.|
Paediatric populationThe 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 (see section 4.2 for information on paediatric use).
DistributionThe 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.
BiotransformationUnchanged 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.
EliminationEribulin 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 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.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 impairmentA study evaluated the pharmacokinetics 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 impairmentIncreased 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.
Unopened vials4 years.
In-use shelf lifeFrom 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.
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