Summary Basis of Decision for Halaven ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
HalavenTM
Eribulin mesylate, 0.5 mg/mL, Solution, Intravenous injection
Eisai Ltd.
Submission control no: 141946
Date issued: 2012-04-26
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02377438
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Control Number: 141946
Date of Submission:
Date of authorization:
HALAVENTM is a trademark owned by Eisai R&D Management Co., Ltd.
2 Notice of decision
On December 14, 2011, Health Canada issued a Notice of Compliance to Eisai Limited for the drug product, Halaven.
Halaven contains the medicinal ingredient eribulin mesylate, which is an antineoplastic agent.
Halaven is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane administered in either the adjuvant or metastatic setting.
The market authorization was based on quality, non-clinical, and clinical information submitted. In an open-label, randomized, multicentre, multinational study of 762 patients with metastatic breast cancer, the efficacy and safety of Halaven were assessed in patients previously treated with a minimum of 2 and a maximum of 5 prior chemotherapy regimens (at least 2 for locally recurrent or metastatic disease), including an anthracycline and a taxane (unless contraindicated). Patients received a median of 4 prior chemotherapy regimens. Patients must have progressed within 6 months of their last chemotherapeutic regimen. The primary endpoint of the study was overall survival. A statistically significant improvement in overall survival was observed in patients randomized to Halaven compared to Treatment of Physician's Choice. An improvement of 2.5 months median survival was demonstrated. The 1-year survival rates were 54% in patients randomized to Halaven and 44% in the Treatment of Physician's Choice group. Two major safety issues were identified in this submission: neutropenia; and QT/QTc interval prolongation. Also, Halaven has not been studied in patients with severe hepatic or renal impairment. These issues have been addressed through appropriate labelling (a Serious Warnings and Precautions box) in the Product Monograph. In addition, peripheral neuropathy was identified as the most common toxicity leading to discontinuation of Halaven. The Halaven treatment may aggravate existing neuropathy. Women should be advised not to become pregnant when taking Halaven as it is expected to cause foetal harm. Halaven is contraindicated for patients with a history of hypersensitivity to Halaven or halichondrin B or its chemical derivatives.
Halaven (0.5 mg/mL eribulin mesylate) is presented as a solution. The recommended dose of Halaven is 1.4 mg/m2 administered intravenously (IV) over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. Patients should have Absolute Neutrophil Count (ANC) values ≥1,500 cells/mm3 and platelets >100,000/mm3 at the initiation of treatment with Halaven. Dosing guidelines are available in the Product Monograph. Halaven should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Halaven are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Halaven is favourable for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane administered in either the adjuvant or metastatic setting.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Eribulin mesylate, the medicinal ingredient of Halaven, is an antineoplastic agent. Halaven is indicated for treatment of metastatic breast cancer in patients who have previously received at least two chemotherapeutic regimens, including an anthracycline and a taxane. Eribulin mesylate functions as a microtubule dynamics inhibitor, inhibiting polymerization and decreasing the microtubule polymer mass in cells. These antimitotic effects prevent cell cycle progression, eventually leading to apoptosis.
Manufacturing Process and Process Controls
Eribulin mesylate is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet International Conference on Harmonisation (ICH) requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of eribulin mesylate has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and were found to be satisfactory.
The sponsor has provided a summary of all drug-related impurities. Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH-established limits and/or were qualified from toxicological studies and therefore, are considered to be acceptable.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of eribulin mesylate are considered acceptable.
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of eribulin mesylate.
The levels of product- and process-related impurities were adequately monitored throughout the manufacturing process. Results from process validation reports and in-process controls indicated that the impurities of the drug substance were adequately under control. The level of impurities reported for the drug substance was found to be within the established limits.
The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed retest period, shelf-life, storage conditions, and shipping conditions for the drug substance were supported and are considered to be satisfactory.
Stability study results based on long-term, accelerated and stress testing show that eribulin mesylate is a stable compound when packaged as proposed over the proposed storage period. The bulk drug is also stable under the proposed storage conditions.
3.1.2 Drug Product
Description and Composition
The drug product, Halaven, is supplied as a sterile, nonpyrogenic, clear and colourless aqueous solution. It is presented in an ammonium-sulfate-treated type I glass vial with a Teflon-2-coated butyl rubber stopper and an aluminum seal.
Each 2 mL vial of product contains: 1.0 mg of eribulin mesylate and the following excipients: alcohol; hydrochloric acid; sodium hydroxide; and water for injection.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of eribulin mesylate with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section included the composition of Halaven, the rationale for choice of formulation, the manufacturing process including packaging, the information on batches used in the in vitro studies for characterization, and a discussion on the effect of formulation change on the safety and/or efficacy of Halaven. Studies which justified the type and proposed concentration of excipients used in the drug product were also reviewed and are considered acceptable.
Manufacturing Process and Process Controls
The drug product is formulated, sterile filtered, aseptically filled into vials and labelled using conventional pharmaceutical equipment and facilities.
All manufacturing equipment, in-process manufacturing steps and detailed operating parameters were adequately described in the submitted documentation and were found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits.
Control of Drug Product
Halaven is tested to verify that its identity, appearance, assay, pH, fill volume, sterility, levels of degradation products, drug-related impurities and bacterial endotoxins are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
Validation reports submitted for all analytical procedures used for in-process and release testing of the drug product are considered satisfactory, and, are in compliance with ICH guidelines.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within ICH-established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.
Stability
Based on the long-term, accelerated, and stress testing stability data submitted, the proposed 48-month shelf-life when stored up to 25°C for Halaven is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in the production of Halaven are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Halaven has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Eribulin mesylate exerts its anticancer effects via a tubulin-based antimitotic mechanism, leading 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. Using purified tubulin incubated under conditions that allowed its spontaneous polymerization, the half-maximal inhibitory concentration (IC50) of eribulin mesylate for rate and extent of inhibition of polymerization was determined to be 15-40 µmol/L. The effect on microtubule dynamics was determined in isolated fractions and cells in culture. In isolated fractions, eribulin mesylate reduced the growth rate and increased the fraction of time the microtubules spent in an attenuated or paused state, but had little apparent effect on the shortening rate. Microtubule dynamic instability was evaluated in MCF7 human breast cancer cells after six hours of incubation with 1 nmol/L eribulin mesylate, a concentration that induced half-maximal accumulation of cells in mitosis and inhibited their proliferation by approximately 50% after 20 hours of incubation. Under these conditions, eribulin mesylate suppressed microtubule growth rate, length, and duration of microtubule growth, but had no effects on microtubule shortening rate, length, or duration.
Inhibition of microtubule growth parameters by eribulin mesylate with a corresponding lack of effect on microtubule shortening parameters is consistent with drug binding to microtubule ends where it prevents the addition of free alpha/beta tubulin heterodimers to the microtubule end, thus slowing microtubule growth.
In vitro studies showed that eribulin mesylate was a potent inhibitor at the sub-nanomolar and nanomolar range in both adherent and non-adherent immortalized cell lines. In both cell lines, eribulin mesylate induced G2/M cell cycle blocks, eventually leading to apoptosis after a prolonged blockage.
As a single agent, eribulin mesylate showed antitumour activity against a wide range of different cancer xenografts implanted subcutaneously in mice. The lowest effective dose in these studies ranged from 0.12 to 1.27 mg/kg.
No secondary pharmacodynamic or drug interaction studies were conducted. However, inhibition of P-glycoprotein (P-gp) by verapamil resulted in an increased inhibition of cell proliferation by eribulin mesylate in a P-gp over-expressing cell line.
At concentrations up to 30 µM, eribulin mesylate did not inhibit the human Ether-a-go-go Related Gene (hERG) tail current in HEK293 cells stably transfected with hERG complementary deoxyribonucleic acid (cDNA) and had no effect on cardiac action potentials in isolated dog Purkinje fibers. Intravenous infusion of eribulin mesylate at 0.01 mg/kg (0.2 mg/m2) for 60 min had no effects on the cardiovascular system or on core body temperature in male and female dogs. Dosing at 0.04 mg/kg (0.8 mg/m2) resulted in transiently decreased systolic, diastolic and mean arterial pressure and heart rate, and increased the RR interval, with the effects in males more pronounced than in females. There were no significant effects on the other lead II electrocardiogram parameters and core body temperature. Evaluation of potential cardiac effects in vitro was conducted at concentrations far exceeding (>300 times) the maximum plasma concentration (Cmax). However, the maximal plasma concentrations achieved in the cardiovascular safety pharmacology study with eribulin mesylate administered as a 1 hour infusion at 0.04 mg/kg (0.8 mg/m2) were approximately 6% of the clinical Cmax. Thus, while in vitro results did not indicate cardiac effects on ion channels at concentrations achievable in the clinical setting, this potential has not been fully characterized in vivo in a non-clinical model.
In in vivo single-dose safety pharmacology studies on the central nervous system (CNS) and respiratory systems in rats, doses of up to 0.25 mg/kg (1.5 mg/m2) had no discernable effects. A comparative neurotoxicity study was conducted in mice. Intravenous doses of eribulin mesylate at doses up to the MTD for two weeks induced no significant reduction in nerve conduction velocity or amplitude in caudal and digital nerves.
3.2.2 Pharmacokinetics
Absorption
After a single IV administration, a dose-proportional increase in exposure was observed in mice and rats. Pharmacokinetic (PK) parameters in mice and dogs were similar after single- and repeat-dose administration, while repeat-dosing in rats resulted in lower PK parameters. Dogs showed considerable variation in PK parameters after repeat-dosing, however, indicating a slow and fluctuating decrease in plasma concentrations post-dose.
Doses of 0.13 and 0.2 mg/kg administered IV every four days for a total of three treatments (Q4Dx3) in rats resulted in severe toxicity; however, the differences in kinetics at 0.2 mg/kg and between Days 1 and 9 may have been a reflection of the poor clinical condition of the rats rather than indication of accumulation.
The oral bioavailability of eribulin was limited (<7%) and distribution into the CNS negligible in wild-type rats and mice. The oral bioavailability of eribulin increased to 52.6% in P-gp-deficient mice and to 18% in rats pretreated with cyclosporine, a P-gp inhibitor. In addition, the penetration of eribulin into the CNS was higher in P-gp-deficient mice compared with wild type. These results are consistent with eribulin being a substrate for the P-gp efflux transporter in vivo.
Eribulin rapidly penetrated a tumour xenograft in an athymic mouse model. The exposure [area under the curve, (AUC)] of eribulin in the tumor increased roughly proportionally with the dose and appeared to be slightly higher after repeat dosing compared with that observed following a single dose. The exposure and estimated half-life of the drug were higher in the tumour than in the plasma, indicating slow elimination from the tumour.
Distribution
The distribution of eribulin was characterized in male albino and male pigmented rats. Approximately half of the tissues reached maximum concentrations at 5 minutes post-dose and most other matrices reached Cmax at 0.5 hours or 6 hours post-dose. The highest tissue concentrations occurred in the lung, urinary bladder, renal cortex, renal medulla, spleen, thyroid, stomach, and salivary gland. Approximately half of the tissues had concentrations below detectable limits by 7 days post-dose and all remaining tissues, except thymus, had concentrations below 0.2 µg equiv/g. The lowest concentrations were in the CNS.
Eribulin mesylate was not found to bind strongly to plasma protein in any species tested, including human, and there was no preferential distribution to the red blood cells in rat and dog.
Metabolism
In vitro studies indicated little to no metabolism of eribulin mesylate by cytochrome P450 (CYP) isoforms. Eribulin mesylate was a substrate and weak inhibitor of CYP3A4 and the likelihood for in vivo interaction at clinically relevant concentrations is remote. Eribulin mesylate was not an inducer of CYP1A, CYP3A, CYP2C9 or CYP2C19 in human hepatocyte monoculture.
In vivo, metabolism appeared to be a minimal route of elimination. Potential metabolites were characterized in plasma, urine, bile (rat only), and faeces of rats and dogs. The parent compound was the major component in all matrices. Six and three minor metabolites were detected in rats and dogs, respectively. The metabolites with the highest concentrations in rats and dogs were assumed to be degradation products and they accounted for 6.4% of the dosed radioactivity in faeces in rats, and 2-4% in dogs.
Excretion
Excretion in the bile and faeces was predominant in both rat and dog, with no apparent difference in pattern of excretion over several doses. Cumulative excretion 10 days after a single dose was 65-85% of the administered dose in faeces, 10-16% in the urine and 13% retained in the carcasses. The majority of the excretion occurred within 48 hours and, in bile-cannulated rats, 36% of the dose was excreted in the bile within 72 hours, most of it with the first 24 hours. Exhalation was not a route of elimination in the rat.
3.2.3 Toxicology
Single-Dose Toxicity
Current guidelines no longer require or recommend stand-alone acute toxicity studies provided adequate repeat-dose toxicity studies have been conducted and the MTD can be estimated. These criteria were fulfilled by this submission.
Repeat-Dose Toxicity
Repeat-dose IV studies were performed in rats and dogs to characterize the general toxicity of eribulin mesylate.
Dose-limiting toxicity in bone marrow in both species as well as gastrointestinal (GI) toxicity in dogs precluded administration of eribulin mesylate on a repeat basis at doses equal to or exceeding the clinically recommended dose. At the doses that could be administered, plasma concentrations were lower than those after clinical exposure. Within the limitations of doses that could be administered, the toxicity of eribulin mesylate has been comprehensively and conventionally evaluated in the rat. The toxicity in the dog was less well characterized; however, as the toxicity of eribulin mesylate is generally consistent with other microtubule inhibitors, and immediate effects have been characterized in the rat, additional studies in the dog were not deemed necessary for this indication.
Effects on bone marrow, lymphoid tissue, testes and GI tract were all consistent with the pharmacological mechanism of action and distribution of eribulin mesylate. The effect on the GI tract was noted in dogs only and occurred at lethal doses. Haematological changes, secondary to effects on bone marrow and lymphoid tissue, were reversible (white blood cells) or showed indications of reversibility (red blood cells). After six cycles of dosing every 7 days for a total of three times (Q7Dx3) with a 14-day non-treatment period, hypocellularity was present in the bone marrow at 0.05 and 0.15 mg/kg in the rat and at 0.045 mg/kg in the dog. Changes in peripheral blood in the chronic studies were consistent with recovery following cessation of dosing. Effects on the testes, noted in both rats and dogs, were not reversed under the conditions of the studies. In rats, testicular atrophy/hypocellularity occurred after a single cycle of Q4Dx3 and Q7Dx3 at ≥0.1-0.13 mg/kg and six cycles of Q7Dx3 at 0.15 mg/kg. In the dog, there were no effects on the testes after one cycle of Q7Dx3 at doses up to 0.035 mg/kg, whereas six cycles of Q7Dx3 at 0.045 mg/kg caused hypocellularity of the seminiferous epithelium with secondary epididymal hypospermia/aspermia.
Neuropathy has been reported after treatment with microtubule inhibitors and although the mechanism has not entirely been established, it is considered related to pharmacological effects on microtubules, structures that are important for the development and maintenance of neurons. There were no histological changes in nerves in the dog study; however, a low incidence of mild fibre degeneration in the sciatic nerve was observed in the rat studies. In addition, degeneration of myocytes in skeletal muscle was noted in rats.
Focal and multifocal necrosis in the liver of male rats after chronic dosing were attributed to bacterial infections and correlated with increases in alanine aminotransferase (ALT) at the high dose (0.15 mg/kg). The effect is considered secondary to the effects on the bone marrow. The ALT value was increased in high-dose females as well but there were no hepatocellular histopathological correlates for the increase. The increase is nevertheless significant and may represent an indirect effect of eribulin mesylate in females as well as males.
Genotoxicity
Eribulin mesylate was not mutagenic in bacterial cells. However, it was highly cytotoxic in mouse lymphoma cells and was weakly positive in a mutation assay with and without S9 activation. Effects were characterized as mutations and/or clastogenic. Single IV doses of 0.05, 0.13, and 0.5 mg/kg (0.3, 0.78 and 3 mg/m2) eribulin mesylate reduced polychromatic erythrocytes and increased micronucleated polychromatic erythrocytes in bone marrow of rats. Micronucleus sizes in treated animals were larger than those induced by a comparator clastogenic agent, and support that the effect was primarily due to chromosome segregation rather than breakage. This pattern of genotoxicity is consistent with an aneugen (an agent causing alterations in chromosome number) and similar effects have been reported with other microtubule inhibitors. Thus, the effects appear related to the mode of action of the drug.
Carcinogenicity
Carcinogenicity studies were not conducted and are not required based on the indication.
Reproductive and Developmental Toxicity
No fertility studies were conducted as part of this submission. However, the general toxicology studies clearly identified the testes as a target tissue and reduced fertility or infertility is to be expected in males. There were no consistent histological indications of effects on the female reproductive tract, and the potential effect on female fertility is unknown. Based on the findings in males, the potential for effects on fertility in a clinical setting have been reflected in the Product Monograph.
The placental transfer of eribulin mesylate has not been characterized. However, embryolethality and teratogenicity in the rat indicate that eribulin mesylate and/or its metabolites pass through the placenta and are distributed to the foetus. The embryo-foetal development rate/period of organogenesis dictated a more frequent dosing schedule in the embryo-foetal development study than that used in the clinical dosing schedule, and thus comparisons with clinical dosing and potential plasma concentrations are not straightforward. However, embryolethality and teratogenicity in rats appear to occur at doses below those used clinically. Because eribulin mesylate is teratogenic in rats and teratogenicity/embryolethality has been reported for other microtubule inhibitors, an embryo-foetal development study in rabbits was not deemed necessary.
Other Studies
In vitro assays for haemotoxicity showed that eribulin mesylate is a potent inhibitor of cell proliferation and cell differentiation of cultured bone marrow mononuclear cells. In a haemotoxicity assays via luminescence output (HALO) assay, inhibition of cell proliferation was similar in human and canine bone marrow cells, whereas mouse cells were approximately 10 times less sensitive. In a colony-forming assay, an endpoint measuring differentiation rather than proliferation, mice also appeared less susceptible to the inhibitory effects of eribulin mesylate than dogs and humans. In cultured human bone marrow mononuclear cells, the IC50 of eribulin mesylate was similar to that of vincristine and lower than that of paclitaxel. The multipotential stem cell population used in these assays was the stem cell population for erythropoietic, myelomonocytic and megakaryopoietic progenitor cells and the results are consistent with significant suppression of all differing haematopoietic lineages. The studies did not include evaluation of the lymphopoietic system since it originates from a more primitive stem cell population than the multipotential stem cell population.
3.2.4 Summary and Conclusion
The PK of eribulin mesylate in mice, rats, and beagle dogs were characterized by an extensive volume of distribution, a moderate clearance, and a relatively slow elimination. The differences in pharmacokinetic parameters between species do not appear significant.
Eribulin is a substrate of the transport protein P-gp in vitro; however, the transport proteins involved in the excretion of eribulin have not been identified. The Product Monograph has been updated to include a statement that caution should be exercised when Halaven is administered with inhibitors of transport proteins.
The repeat-dose toxicity studies have characterized the expected toxicity associated with microtubule inhibitors. Bone marrow effects with secondary hematological peripheral changes show reversibility, whereas testicular effects and changes in peripheral nerves were not shown to be reversible. In addition, skeletal muscle and potentially liver were target organs. These changes occurred at and below clinical dose on a mg/m2 and plasma exposure basis. The changes in bone marrow, skeletal muscle and liver can be monitored in clinical setting and effects on peripheral nerve have been described with other microtubule inhibitors. Warnings regarding the potential for effects on male reproductive organs and pregnant women have been added to the Product Monograph. The effect on the cardiovascular system does not indicate any changes histopathologically; however, potential functional changes have not been evaluated in the dog in the chronic study or acutely at plasma concentrations exceeding those to be used clinically.
Overall, the toxicity profile for eribulin mesylate in the non-clinical studies is as expected for this class of compounds, and no major unanticipated toxicities were identified.
3.3 Clinical basis for decision
Evaluation reports from the United States Food and Drug Administration (FDA) and European Medicines Agency, obtained through the FDA website and the sponsor, respectively, were consulted extensively during this review. The United States information labelling and the European Summary of Product Characteristics for Halaven were consulted during the review of the clinical efficacy and safety.
3.3.1 Pharmacodynamics
A total of 31 patients from five investigational centres were enrolled in a QT interval prolongation study. Patients had a variety of cancer types and almost all were with metastatic disease and heavily pre-treated. Of these, 26 patients received 1.4 mg/m2 eribulin mesylate by IV infusion on Days 1 and 8 every three weeks. Two patients were discontinued from the study before completion due to adverse events and progression of disease, respectively. No effect on the QTc interval was observed on Day 1. On Day 8 of treatment, QTc interval prolongation was observed. The largest mean increase from baseline was 10.5 msec [90% confidence interval (CI): 4.9, 16.2]. The exposure to Halaven was similar on Day 1 and Day 8; therefore, differences in plasma concentration could not account for the delayed increase in the QTc interval.
3.3.2 Pharmacokinetics
The proposed dose of Halaven is 1.4 mg/m2 eribulin mesylate administered intravenously (IV) over 2-5 minutes on Days 1 and 8 of a 21-day cycle. Eribulin demonstrated linear PK in the dose range of 0.25-4 mg/m2, characterized by a rapid distribution phase followed by a prolonged elimination phase. The mean terminal half-life was 40 hours. Eribulin did not accumulate after multiple dose administrations. The mean exposure (AUC) ranged from 600 to 971 ng/hr/mL and the Cmax ranged from 186 to 519 ng/mL.
Distribution
Eribulin demonstrated a large volume of distribution at steady state (Vss, 43-114 L/m2). Protein binding of eribulin in human plasma was 49-65% and there was minimal preferential distribution into the red blood cells.
Metabolism
Unchanged eribulin was the major circulating species in human plasma. Metabolites represented less than 0.6% of the parent compound. In vitro, CYP3A4 was the major enzyme responsible for the metabolism of eribulin in human liver microsomes. However, CYP-mediated metabolism of eribulin appeared to be minor. Eribulin showed low plasma clearance (CL, 1.16 L/h/m2 to 2.42 L/h/m2).
Excretion
Elimination was primarily through biliary excretion of unchanged drug. After administration of radiolabelled eribulin to patients, approximately 82% of the dose was eliminated in faeces. Unchanged eribulin accounted for approximately 88% of the radioactive materials recovered in faeces. Renal clearance was not a significant route of eribulin elimination (<10%).
Drug Interactions
Eribulin exposure was not influenced when Halaven was administered concomitantly with ketoconazole, a CYP3A4 inhibitor. The results of a drug-drug interaction study demonstrated that rifampicin, a CYP3A4 inducer, had no effect on the PK parameters of eribulin. This finding was confirmed by a population PK study showing that there was no effect on the exposure of eribulin when administered in combination with CYP3A4 inhibitors or inducers.
In non-clinical evaluations, eribulin did not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 or induce CYP1A2, CYP2C9, CYP2C19, or CYP3A4 enzymes at relevant clinical concentrations. Therefore, Halaven is not expected to alter the plasma concentrations of drugs that are substrates of these enzymes.
Special Populations
Age, gender, and race did not have a significant effect on the PK of eribulin.
Hepatic impairment affected the disposition of eribulin, resulting in increased exposure. For patients with mild and moderate hepatic impairment, the AUC was increased 1.75 and 2.79 times, respectively. The Product Monograph has been revised to recommend dose adjustments for patients with mild and moderate hepatic impairment (1.1 mg/m2 and 0.7 mg/m2 of Halaven, respectively). Patients with severe hepatic impairment (Child-Pugh C) were not evaluated and should not be treated with eribulin mesylate.
Eribulin clearance in patients with mild or moderate renal impairment was compared with that in patients with normal renal function. Patients with severe renal impairment were not evaluated. Even though the sponsors stated that renal impairment has no effect on the clearance of eribulin, a visual trend was observed. Patients with moderate renal impairment showed a 2-fold decrease in clearance and a 2-fold increase in AUC. Thus, the Product Monograph has been revised to alert physicians that patients with moderate renal impairment may need a reduction in dose and that caution and close monitoring of adverse reactions, particularly myelosuppression, should be applied for this patient population.
Overall, this proposed dose and schedule had good tolerability in the Phase I studies. The clinical pharmacology data are considered sufficient and indicate no major concerns in the use of eribulin mesylate for the requested indication.
3.3.3 Clinical Efficacy
The efficacy findings were derived from one pivotal Phase III clinical study and two supporting Phase II studies. The Phase III study was an open-label, randomized, multicentre, multinational, active-controlled study of 762 patients with metastatic breast cancer previously treated with at least two chemotherapeutic regimens. Patients must have progressed within 6 months of their last chemotherapeutic regimen. Patients were randomized 2:1 to receive Halaven (1.4 mg/m2 IV over 2-5 minutes on Days 1 and 8 in a 21-day cycle) or treatment of physician's choice (TPC). The TPC treatment could include single-agent chemotherapy, hormonal treatment, biologic therapy, palliative treatment or radiotherapy, administered as per standard protocol. For this study, TPC was 97% chemotherapy and 3% hormonal therapy.
Overall survival (OS) was the primary endpoint, and was significantly improved compared with TPC [hazard ratio (HR) = 0.809, 95% CI: 0.660 to 0.991, probability (p) = 0.041]; median survival was increased by 75 days [399 versus (vs.) 324 days]. The OS-update analysis of the pivotal study was consistent with the primary analysis. Median OS was 403 days (95% CI: 367 to 438) in the Halaven-treated group and 321 days (95% CI: 281 to 365) in the TPC-treated group. The HR was 0.805 (95% = 0.014). In the population of patients with measurable disease at baseline (682 patients), the objective response rate (ORR), a secondary endpoint, was statistically higher in the Halaven group compared with the TPC group (12.2% vs. 4.7%; p = 0.002). Halaven showed a good ORR considering the late stage of the disease of the patients in this study. These efficacy findings are statistically significant and clinically relevant.
The Phase III study results were supported by those from two single-arm Phase II studies (number of patients = 403) in a similar population at the recommended dose.
Patients with locally advanced breast cancer were not studied in the pivotal study. Therefore, the proposed indication in the Product Monograph has been modified to restrict the use to "patients with metastatic breast cancer" only.The indication has also been revised to indicate that the prior therapies should have included an anthracycline and taxane therapies in either the adjuvant or metastatic setting.
The risk for drug interactions affecting efficacy is low since eribulin is minimally metabolized by liver enzymes.
The amount of long-term data is limited, but this is acceptable considering the late-stage disease setting of the proposed patient population. The efficacy of Halaven in patients aged ≤40 years or aged >65 years has not been clearly demonstrated.
The recommended dose and schedule (the IV administration of 1.4 mg/m2 over 2-5 minutes on Days 1 and 8 of a 21-day cycle) are acceptable since they reflect the dose administered in the pivotal study, for which Halaven efficacy has been demonstrated.
3.3.4 Clinical Safety
The safety evaluation of Halaven was primarily based on the pivotal study described in section 3.3.3 Clinical Efficacy. In total, 1,165 patients were enrolled into the pivotal and non-pivotal studies (762, 299, and 104 patients, respectively). Of these, 827 patients received at least one dose of Halaven at the proposed label dose and schedule. The median duration of exposure was 118 days. The number (%) of Halaven patients on treatment for >6 months was 114 (22.7%), and 12 (2.4%) for >1 year.
The toxicity profile was acceptable with the most commonly reported adverse effects (AEs) in the pivotal study being asthenia/fatigue (53.7%), neutropenia (51.7%), alopecia (44.5%), peripheral neuropathy (34.6%), nausea (34.6%), constipation (24.7%), and leukopenia (23.1%). The incidence of these events was similar in the pooled patient population.
In the Halaven group of the pivotal study, Grade 3 and Grade 4 neutropenia was observed in 21.1% and 24.1% of patients, respectively. Neutropenia was reversible in most patients. Although the observed haematologic toxicity was relatively frequent and severe, it proved to be manageable with dose delays, dose reductions, and the use of growth factors. Neutropenia occurred in approximately half the pooled patient population treated with Halaven but led to febrile neutropenia in 4.6% of cases. Patients with ALT or aspartate amiotransferase (AST) >3 x the upper limit of normal (ULN) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia. Although data are limited, subjects with bilirubin >1.5 x ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia. Septic death was also observed in some of these patients.
In the pivotal study, adverse drug reactions (ADRs) leading to discontinuation were reported for 67 (13.3%) patients in the Halaven-treated group and 38 (15.4%) in the TPC group. The most common AE that led to discontinuation of Halaven was peripheral neuropathy (4.8%). The most common ADRs leading to clinical intervention [that is (i.e.) dose adjustment or concomitant medication to treat an ADR symptom] were: neutropenia; nausea; constipation; pyrexia; peripheral neuropathy; arthralgia/myalgia; anemia; back pain; headache, and leukopenia.
Peripheral neuropathy occurred frequently with Halaven (about 1/3 of the subjects in the Breast Cancer Population), although development of severe symptoms (Grade 3 and 4) was reported in <8% of patients and approximately 5% of the patients discontinued study therapy owing to peripheral neuropathy. Patients with pre-existing neuropathy Grade ≤2 and prior history of diabetes did not experience a higher incidence of peripheral neuropathy during treatment with Halaven compared with patients without pre-existing peripheral neuropathy; however, they did experience a higher frequency of Grade 3 neuropathy (12.6% vs. 7.0%). Therefore, pre-existing peripheral neuropathy deteriorated in some patients, thus these patients are considered to be at higher risk.
Treatment-emergent serious adverse events (SAEs) were reported for approximately 27% of the pooled patient population (25% in the pivotal study).The most frequently reported SAEs in the Halaven group were febrile neutropenia and neutropenia.
Because of potential increased exposure to eribulin, a dose reduction to 0.7 mg/m2 to patients with moderate hepatic impairment (Child-Pugh B) is recommended. A dose reduction to 1.1 mg/m2 for patients with mild hepatic impairment (Child-Pugh A) is also recommended. However, the potential of severe drug-induced hepatotoxicity from Halaven is considered low.
Based on the population PK analysis, mild [creatinine clearance (CrCl): 50-80 mL/min] or moderate renal impairment (CrCl: 30-50 mL/min) could cause increased eribulin mesylate exposure. Patients with severe renal impairment (CrCl: <30 mL/min) were not evaluated in the pivotal study. Due to 2-fold increase in exposure (AUC) to eribulin mesylate, patients with moderate renal impairment may need a lower starting dose. Caution and close monitoring of adverse reactions, particularly myelosuppression, is advised for patients with renal impairment.
Of the pooled safety data from patients receiving the proposed dose of Halaven, 39 deaths were reported. The causes of death were most commonly related to disease progression and were not unexpected given the advanced disease of this subject population. However, 6 deaths were reported as possibly or probably treatment-related. Infection-related SAEs (febrile neutropenia with septic shock, pulmonary infection, bronchopneumonia, sepsis due to tumoural infection) were the cause of death in 4 patients treated with Halaven in the pivotal study and 1 patient in a non-pivotal study. The relationship between these deaths and Halaven cannot be excluded. Neutropenia is associated with Halaven and these observations suggest that neutropenia may lead to a fatal outcome in some Halaven-treated patients.
Halaven 1.4 mg/m2 IV was associated with QTcB prolongation at all time points, with statistically significant increases at many time points, in spite of poor precision of measurements. Using heart rate corrections, clinically significant increases (10.5-13.30 ms) in QTc were observed at 6 hours post-dosing. These results indicate that Halaven may potentially increase the risk of torsade de pointes. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death. There is thus a potential risk for drug interactions with other QT/QTc prolonging drugs.
Halaven was also associated with decreased serum potassium concentrations. The occurrence of hypokalaemia in conjunction with QTc prolongation creates a heightened risk of proarrhythmia. Hypokalaemia should be corrected before administering Halaven. Electrolytes should be monitored periodically during therapy.
Population PK analyses showed that eribulin mesylate exposure in elderly subjects was similar to that in younger subjects. No specific dose adjustments are recommended based on age of the subject and the tolerability of Halaven was acceptable in elderly subjects.
There are no adequate and well-controlled studies with Halaven in pregnant women. Nevertheless, based on its mechanism of action and on non-clinical findings, Halaven is expected to cause foetal harm when administered to pregnant women. It is not known whether Halaven is excreted into human milk, but because many drugs are excreted into human milk, there is a potential for serious adverse reactions in nursing infants from Halaven exposure.
Overall, the observed safety profile of Halaven was acceptable for a chemotherapeutic agent in late line settings and the drug was generally well-tolerated.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Metastatic breast cancer is a life-threatening disease. The benefit of Halaven for patients with metastatic breast cancer who have received at least two chemotherapeutic regimens for the treatment of metastatic disease is meaningful. It significantly improves overall survival in this patient population and the adverse drug reactions are clinically manageable. The labelling information accurately reflects the safety, efficacy and quality assessments. The benefit/risk profile for the administration of Halaven for the stated indication is highly favourable. Although Halaven is deemed a toxic chemotherapeutic drug, the risks are considered manageable when used according to the recommendations stated in the Product Monograph.
A risk management plan has been assessed and necessary revisions have been communicated to the sponsor.
The sponsor has confirmed that the results of the following studies will be provided to Health Canada when they become available:
- Study E7389-A001-106 (Renal Impairment), An Open-Label Phase I Study to Assess the Pharmacokinetics and Safety of Halaven in Subjects with Cancer Who also Have Impaired Renal Function. The planned submission date is within the first quarter (Q1) of 2015.
- Study E7389-G000-209 (Neuropathy), A Phase II, Multicentre, Randomized, Open-Label Study Comparing Eribulin Mesylate and Ixabepilone in Causing or Exacerbating Neuropathy in Patients with Advanced Breast Cancer. The planned submission date is Q2, 2012.
- Study E3789-G000-301, A Phase III Open Label, Randomized Two-Parallel-Arm Multicentre Study of E3789 Versus Capecitabine in Patients with Locally Advanced or Metastatic Breast Cancer Previously Treated with Anthracyclines and Taxanes. The planned submission date is Q1, 2013.
- Study E3789-G000-305 Update Report, Results for Overall Survival After 95% of Patient Deaths have Occurred). The planned submission date is Q3 2013.
The safety of Halaven in patients with impaired renal functions or in patients who developed neuropathy is appropriately managed by the Product Monograph warnings. However, the results of the Studies E7389-A001-106 and E7389-G000-209 should provide a better knowledge of the safety of Halaven in patients with impaired renal functions and on the development and reversibility of Halaven-induced neuropathy. In addition, although the dossier provides convincing evidence of efficacy for the proposed indication, the results of the last two studies should confirm the efficacy of Halaven in patients with previously treated metastatic breast cancer.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Halaven is favourable in the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane administered in either the adjuvant or metastatic setting. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: HalavenTM
| Submission Milestone | Date |
|---|---|
| Request for priority status | |
| Filed: | 2010-09-27 |
| Rejection issued by Director, Bureau of Metabolism, Oncology, and Reproductive Sciences: | 2010-11-16 |
| Submission filed: | 2010-12-31 |
| Screening | |
| Screening Acceptance Letter issued: | 2011-02-18 |
| Review | |
| Quality Evaluation complete: | 2011-12-13 |
| Clinical Evaluation complete: | 2011-12-14 |
| Biostatistics Evaluation complete: | 2011-10-19 |
| Labelling Review complete: | 2011-12-14 |
| Notice of Compliance issued by Director General: | 2011-12-14 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| HALAVEN | 02377438 | EISAI LIMITED | ERIBULIN MESYLATE 0.5 MG / ML |