Halaven

Eribulin mesylate.

Each vial contains 1.0 mg of eribulin mesylate equivalent to 0.88 mg eribulin.
Excipients/Inactive Ingredients: Ethanol, Water for Injections.

Pharmacotherapeutic Group: Other antineoplastic agents. ATC Code: L01XX41.
Pharmacology: Pharmacodynamics: HALAVEN (Eribulin mesylate) is a tubulin-targeted, non-taxane microtubule dynamics inhibitor that is a structurally simplified, synthetic analogue of the marine natural product halichondrin B.
Mechanism of action: Eribulin mesylate is a tubulin-targeted antimitotic agent that exerts its antiproliferative effects on cancer cells via a mechanistically novel mode of inhibition of microtubule dynamics. Such inhibition leads to G₂/M (Gap 2/mitosis stages of cell cycle) cell cycle blocks, disruption of mitotic spindles, and ultimately apoptotic cell death after prolonged mitotic blockage.
In addition, eribulin treatment of human breast cancer cells caused changes in morphology and gene expression as well as decreased migration and invasiveness in vitro. In mouse xenograft models of human breast cancer, eribulin treatment was associated with increased vascular perfusion and permeability in the tumor cores, resulting in reduced tumor hypoxia, and changes in the expression of genes in tumor specimens associated with a change in phenotype.
Clinical experience: Breast cancer: The efficacy of HALAVEN in breast cancer is supported by two single-arm Phase 2 studies in 403 patients and the randomized Phase 3 comparative study in 762 patients. The patients in the pivotal 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).
In the pivotal Phase 3 EMBRACE study, patients must have progressed within 6 months of their last therapeutic regimen. They were randomized 2:1 to receive either HALAVEN (1.4 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 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). (See Table 1 and Figure 1.)

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At the time of the original data cut-off, the PFS and ORR results according to independent and investigator's assessment are described in the following tables: (See Tables 2 and 3.)

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Liposarcoma: In liposarcoma the efficacy of eribulin is supported by the pivotal Phase 3 sarcoma study (Study 309). The patients in this study (n=452) had locally recurrent, inoperable and/or metastatic soft tissue sarcoma of one of two subtypes - leiomyosarcoma or liposarcoma. Patients had received at least two prior chemotherapy regimens, one of which must have been an anthracycline (unless contraindicated).
Patients must have progressed within 6 months of their last chemotherapeutic regimen. They were randomized 1:1 to receive either eribulin 1.23 mg/m² on days 1 and 8 of a 21 day cycle or dacarbazine 850 mg/m², 1000 mg/m² or 1200 mg/m² (dose determined by the investigator prior to randomization), every 21 days.
In Study 309, a statistically significant improvement in OS was observed in patients randomized to the eribulin arm compared to the control arm. This translated into a 2 month improvement in median OS (13.5 months for eribulin treated patients vs. 11.5 months for dacarbazine treated patients). There was no significant difference in progression-free survival or overall response rate between the treatment arms in the overall population.
Treatment effects of eribulin were limited to patients with liposarcoma (45% dedifferentiated, 37% myxoid/round cell and 18% pleomorphic in Study 309) based on pre-planned subgroup analyses of OS and PFS. There was no difference in efficacy between eribulin and dacarbazine in patients with advanced or metastatic leiomyosarcoma. (See Table 4 and Figures 2 and 3.)

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Pharmacokinetics: 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 hr. It has a large volume of distribution (range of means 43 to 114 L/m²) and low clearance (range of means 1.16 to 2.42 L/hr/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: Cytochrome P450 3A4 (CYP3A4) is the major enzyme responsible for the human hepatic metabolism of eribulin. Eribulin (0.05 to 5μM) did not show induction potential for CYP1A and CYP3A in human primary hepatocytes. No significant inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP2E1 was detected with eribulin at concentrations up to 5 μM in pooled human liver microsomes. Therefore, at the current recommended human dose eribulin is unlikely to affect plasma levels of drugs that are substrates of CYP enzymes.
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 is eliminated primarily in faeces. 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. Based on the population PK analysis, renal impairment is not expected to significantly influence eribulin exposure.
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. Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m² to patients with mild hepatic impairment and 0.7 mg/m² to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m² to patients with normal hepatic function. HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C).
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 I 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. Creatinine clearance was estimated with the Cockcroft-Gault formula. A 1.5-fold (90% Cl: 0.9-2.5) higher dose-normalised AUC_(0-inf) was observed in patients with moderate and severe renal impairment. See Dosage & Administration for treatment recommendations.
Toxicology: Preclinical safety data: The nonclinical safety of eribulin mesylate has been evaluated in the following studies: safety pharmacology, repeated toxicity including chronic toxicity, genotoxicity, and reproductive toxicity studies. No significant adverse effects were observed in any safety pharmacology studies except for transient decreases in blood pressure and heart rate in conscious dogs. Results from the toxicology studies showed that the target organ of toxicity is limited to the bone marrow, skeletal muscle, peripheral nerves, gastrointestinal system, and testes. Most of these observed toxic effects were partially or completely reversible by 2 to 4 weeks of recovery. In addition, eribulin mesylate, like other cytotoxic agents, is genotoxic and teratogenic.

HALAVEN 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. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.
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 Pharmacology: Pharmacodynamics under Actions).

HALAVEN should be administered only under the supervision of a qualified physician experienced in the appropriate use of cytotoxic drugs.
The recommended dose of HALAVEN as the ready to use solution is 1.4 mg/m² which should be administered intravenously over 2-5 minutes on Days 1 and 8 of every 21-day cycle.
Dose delays during therapy: Delay the administration of HALAVEN 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: Patients should be clinically evaluated during treatment by physical examination and laboratory testing including complete blood counts (see Precautions). If Grade 3 or 4 toxicities are present, then treatment should be delayed to allow recovery. Patients should only be retreated when the ANC is ≥ 1 x 10⁹/l and platelets are ≥ 75 x 10⁹/l and all other toxicity from a previous cycle has recovered to Grade 2 or less.
Dose reduction recommendations for retreatment are shown in the following table. If toxicities reoccur, an additional dose reduction should be made as shown. (See Table 5.)

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Do not re-escalate the HALAVEN dose after it has been reduced.
Patients with hepatic impairment: Impaired liver function due to metastases: The recommended dose of HALAVEN in patients with mild hepatic impairment (Child-Pugh A) is 1.1 mg/m² administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. The recommended dose of HALAVEN in patients with moderate hepatic impairment (Child-Pugh B) is 0.7 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 HALAVEN 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.
Paediatric patients: HALAVEN is not recommended for use in patients below age 18 years due to insufficient data on safety and efficacy.
Elderly patients: Clinical studies did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. There was no evidence to suggest that the safety profile of HALAVEN is different in elderly patients. No specific dose adjustments are recommended based on the age of the patient (see Adverse Reactions).
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 Pharmacology: Pharmacokinetics under Actions.)
Method of administration: HALAVEN 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 Special precautions for disposal and other handling under Cautions for Usage. 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 Special precautions for disposal and other handling under Cautions for Usage.

In one case of overdose the patient inadvertently received 8.6 mg of eribulin mesylate (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 HALAVEN 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.

Hypersensitivity to the active substance or to any of the excipients; Breast feeding.

Haematology: Myelosuppression is dose dependent and primarily manifested as neutropenia (see Adverse Reactions).
Monitoring of complete blood counts should be performed on all patients prior to each dose of HALAVEN. Treatment with HALAVEN 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 HALAVEN. Patients experiencing febrile neutropenia, severe neutropenia or thrombocytopenia, should be treated according to the recommendations in Dosage & Administration.
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 Pharmacology: Pharmacodynamics under Actions).
Peripheral neuropathy: Peripheral neuropathy commonly occurs and is usually of mild to moderate severity. Monitor patients closely for signs of peripheral motor and sensory neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paraesthesia, discomfort or neuropathic pain. Peripheral neuropathy should be treated according to the recommendations in Dosage & Administration.
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, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalaemia, hypocalcaemia or hypomagnesaemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
HALAVEN may cause side effects 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 and use machinery if they feel tired or dizzy.

Women of childbearing age must be advised to avoid becoming pregnant whilst they or their male partner are receiving HALAVEN and should use effective contraception during and up to 3 months after treatment.
Pregnancy: There is no information on the use of HALAVEN in pregnant women. Eribulin is embryotoxic, foetotoxic, and teratogenic in rats, and testicular toxicity has been revealed in rats and dogs (see Pharmacology: Toxicology: Preclinical safety data under Actions). 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.
Breastfeeding: There is insufficient information on the excretion of eribulin or its metabolites in human or animal breast milk. A risk to newborn or infants cannot be excluded and therefore HALAVEN should not be used during breast feeding (see Contraindications).
Fertility: Male patients should seek advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with HALAVEN.

The most commonly reported adverse reactions to HALAVEN are shown in the table as follows.
The following 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.
Frequencies 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), very rare (< 1/10,000) and not known (cannot be estimated from the available data). 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. (See Table 6.)

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In the same breast cancer population in clinical trials the following medically significant adverse reactions were reported as uncommon (≥ 1/1,000 to < 1/100): Infection and Infestations: Pneumonia, Neutropenic sepsis.
Vascular Disorders: Thrombosis (including DVT and Pulmonary embolism).
Hepatobiliary Disorders: Hepatic disorder.
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.
Haematologic toxicities resulted in discontinuation in <1% of patients receiving HALAVEN.
Neuropathy: In the 1559 breast cancer patients the most common adverse reaction resulting in discontinuation of treatment with HALAVEN 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%.
Special populations: Elderly Population: In studies of 1559 patients treated with HALAVEN, 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 HALAVEN in elderly patients (≥65 years of age) was similar to that of patients ≤65 years of age except for astenia/fatigue which showed an increasing trend with age. No dose adjustments are recommended based on the age of the patient.
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 Precautions and Pharmacology: Pharmacokinetics under Actions.

No drug-drug interactions are expected with CYP3A4 inhibitors, CYP3A4 inducers or P-gp inhibitors. The effect of ketoconazole, a strong inhibitor of CYP3A4 and a P-gp inhibitor, on the pharmacokinetics of eribulin was studied in an open-label, two-treatment, two-sequence, two-way crossover trial in 12 patients with advanced solid tumours. The mean dose-normalized AUC values were similar when eribulin was administered with or without ketoconazole (ratio of the mean AUC: 0.97; 90% CI: 0.83, 1.12). Eribulin exposure (AUC and C_max) was also unaffected by rifampicin, a CYP3A4 inducer.
Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant concentrations. Eribulin is not expected to alter the plasma concentrations of drugs that are substrates of these enzymes.
At relevant clinical concentrations, eribulin did not inhibit BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1 and OATP1B3 transporter-mediated activity.

Special precautions for disposal and other handling: Any unused product or waste material should be disposed of in accordance with local requirements.
HALAVEN is a cytotoxic anticancer medicinal product and, as with other toxic compounds, caution should be exercised in handling HALAVEN. The use of gloves, goggles, and protective clothing is recommended. If the solution contacts the skin, the skin 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. 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. It must not be mixed with other medicinal products and should not be diluted in glucose 5% infusion solution.
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
HALAVEN solution for injection should not be diluted in glucose 5% infusion solution.

To be stored at room temperature (15°C - 25°C).
For storage condition of the diluted medicinal product, see Shelf-Life as follows.
Shelf-Life: From a microbiological point of view HALAVEN should be used immediately. The product is not intended to be stored after opening or after dilution unless this has taken place under controlled and validated aseptic conditions. 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 (0.02 mg/ml to 0.2 mg/ml in sterile sodium chloride 9 mg/ml (0.9%) solution for injection should not be stored longer than 24 hours at 2-8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

Cytotoxic Chemotherapy

L01XX41 - eribulin ; Belongs to the class of other antineoplastic agents. Used in the treatment of cancer.

POM