Eribulin Mesylate Taj Pharma 0.44 mg/ml solution for injection

1. Name of the medicinal product

Eribulin Mesylate Taj Pharma 0.44 mg/ml solution for injection

2. Qualitative and quantitative composition

Each 2 ml vial contains:
Eribulin (as mesylate) 0.88mg
For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection (injection)

4. Clinical particulars

4.1 Therapeutic indications

Eribulin Mesylate is indicated for the treatment of adult patients with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease (see section 5.1). Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting unless patients were not suitable for these treatments.

Eribulin Mesylate is indicated for the treatment of adult patients with unresectable liposarcoma who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease (see section 5.1).

4.2 Posology and method of administration

Eribulin Mesylate should only be administered under the supervision of a qualified physician experienced in the appropriate use of cytotoxic medicinal products.

Posology

The 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 trials, the corresponding publications 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 therapy

The administration of Eribulin Mesylate 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 therapy

Dose reduction recommendations for retreatment are shown in the following table.

Dose reduction recommendations

The dose of Eribulin should not be re-escalated after it has been reduced.

Patients with hepatic impairment

Impaired liver function due to metastases

The 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 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.

Patients with renal impairment

Some patients with moderately or severely impaired renal function (creatinine clearance <50 ml/min) may have increased Eribulin exposure and may need a reduction of the dose. For all patients with renal impairment, caution and close safety monitoring is advised. (See section 5.2)

Elderly patients

No specific dose adjustments are recommended based on the age of the patient (see section 4.8).

Paediatric population

There is no relevant use of Eribulin Mesylate in children and adolescents for the indication of breast cancer.

The safety and efficacy of Eribulin Mesylate in children from birth to 18 years of age have not yet been established in soft tissue sarcoma. No data are available.

Method of administration

Eribulin Mesylate 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.

4.3 Contraindications

– Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

– Breast-feeding

4.4 Special warnings and precautions for use

Haematology

Myelosuppression 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 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.

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 section 5.1).

Peripheral neuropathy

Patients 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 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 or concomittant treatment with medicinal products known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Hypokalaemia, hypocalcaemia or hypomagnesaemia should be corrected prior to initiating Eribulin Mesylateand these electrolytes should be monitored periodically during therapy. Eribulin should be avoided in patients with congenital long QT syndrome.

Excipients

This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per dose.

4.5 Interaction with other medicinal products and other forms of interaction

Eribulin is mainly (up to 70%) eliminated through biliary excretion. The transport protein involved in this process is unknown. Eribulin is not a substrate of breast cancer resistance protein (BCRP), organic anion (OAT1, OAT3, OATP1B1, OATP1B3), multi-drug resistance-associated protein (MRP2, MRP4) and bile salt export pump (BSEP) transporters.

No drug-drug interactions are expected with CYP3A4 inhibitors and inducers. Eribulin exposure (AUC and C_max) was unaffected by ketoconazole, a CYP3A4 and P glycoprotein (Pgp) inhibitor, and rifampicin, a CYP3A4 inducer.

Effects of Eribulin on the pharmacokinetics of other medicines

In vitro data indicate that Eribulin is a mild inhibitor of the important drug metabolising enzyme CYP3A4. No in vivo data are available. Caution and monitoring for adverse 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.

At relevant clinical concentrations, Eribulin did not inhibit BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1 and OATP1B3 transporter-mediated activity.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of Eribulin in pregnant women. Eribulin is embryotoxic, foetotoxic, and teratogenic in rats. Eribulin Mesylate 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 Eribulin Mesylate and have to use effective contraception during and up to 3 months after treatment.

Breast-feeding

It is unknown whether Eribulin/metabolites are excreted in human or animal breast milk. A risk to newborns/infants cannot be excluded and therefore ERIBULIN MESYLATE must not be used during breast-feeding (see section 4.3).

Fertility

Testicular 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 Eribulin Mesylate

4.7 Effects on ability to drive and use machines

Eribulin Mesylate may cause adverse reactions such as tiredness and dizziness which may lead to minor or moderate influence on the ability to drive or use machines. Patients should be advised not to drive or use machines if they feel tired or dizzy.

4.8 Undesirable effects

Summary of safety profile

The most commonly reported adverse reactions related to Eribulin Mesylate, 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 reactions

Unless otherwise noted, the 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.

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.

^a Includes Grade 5 events.

^b From spontaneous reporting

^c Includes preferred terms of peripheral neuropathy, peripheral motor neuropathy, polyneuropathy, paraesthesia, peripheral sensory neuropathy, peripheral sensorimotor neuropathy and demyelinating polyneuropathy

^d No Grade 4 events

* Rare

** Frequency not known

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.

Neutropenia resulted in discontinuation in < 1% of patients receiving Eribulin.

Disseminated intravascular coagulation

Cases of disseminated intravascular coagulation have been reported, typically in association with neutropenia and/or sepsis.

Peripheral neuropathy

In the 1559 breast cancer patients the most common adverse reaction resulting in discontinuation of treatment with Eribulin was peripheral neuropathy (3.4%). The median time to Grade 2 peripheral neuropathy was 12.6 weeks (post 4 cycles). Out of the 404 sarcoma patients, 2 patients discontinued treatment with Eribulin due to peripheral neuropathy. The median time to Grade 2 peripheral neuropathy was 18.4 weeks.

Development of Grade 3 or 4 peripheral neuropathy occurred in 7.4% of breast cancer patients and 3.5% of sarcoma patients. In clinical trials, patients with pre-existing neuropathy were as likely to develop new or worsening symptoms as those who entered the study without the condition.

In breast cancer patients with pre-existing Grade 1 or 2 peripheral neuropathy the frequency of treatment-emergent Grade 3 peripheral neuropathy was 14%.

Hepatotoxicity

In some patients with normal/abnormal liver enzymes prior treatment with Eribulin, increased levels of liver enzymes have been reported with initiation of Eribulin treatment. Such elevations appeared to have occurred early with Eribulin treatment in cycle 1 – 2 for the majority of these patients and whilst thought likely to be a phenomenon of adaptation to Eribulin treatment by the liver and not a sign of significant liver toxicity in most patients, hepatotoxicity has also been reported.

Special populations

Elderly population

Of the 1559 breast cancer patients treated with the recommended dose of Eribulin, 283 patients (18.2%) were ≥ 65 years of age. In the 404 sarcoma patient population, 90 patients (22.3%) treated with Eribulin were ≥ 65 years of age. The safety profile of Eribulin in elderly patients (≥ 65 years of age) was similar to that of patients <65 years of age except for asthenia/fatigue which showed an increasing trend with age. No dose adjustments are recommended for the elderly population.

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 also sections 4.2 and 5.2).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose

In one case of overdose the patient inadvertently received 7.6 mg of Eribulin (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 Eribulin 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.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other antineoplastic agents.

Eribulin Mesilate is a microtubule dynamics inhibitor belonging to the halichondrin class of antineoplastic agents. It is a structurally simplified synthetic analogue of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai.

Eribulin inhibits the growth phase of microtubules without affecting the shortening phase and sequesters tubulin into non-productive aggregates. Eribulin exerts its effects via a tubulin-based antimitotic mechanism leading to G₂/M cell-cycle block, disruption of mitotic spindles, and, ultimately, apoptotic cell death after prolonged and irreversible mitotic blockage.

Clinical efficacy

Breast cancer

The efficacy of Eribulin Mesylate 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 Eribulin Mesylate, 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 Eribulin Mesylate (Taj Pharma 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:

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.

Study 309 – Overall Survival in the Liposarcoma Subgroup

Study 309 – Progression Free Survival in the Liposarcoma Subgroup

Paediatric population

The 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).

The European Medicines Agency has deferred the obligation to submit the results of studies with  Eribulin Mesylate in one or more subsets of the paediatric population for the treatment of rhabdomyosarcoma and non-rhabdomyosarcoma soft tissue sarcoma. See section 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

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 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.

Biotransformation

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 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 C_max). 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 impairment

A 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 ERIBULIN MESYLATE 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. Eribulin Mesylate (Taj Pharma 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 impairment

Increased Eribulin exposure was seen in some patients with moderately or severely impaired renal function, with high between-subject variability. The pharmacokinetics of Eribulin were evaluated in a Phase 1 study in patients with normal renal function (Creatinine clearance: ≥ 80 ml/min; n=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% 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.

5.3 Preclinical safety data

Eribulin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test). Eribulin was positive in the mouse lymphoma mutagenesis assay and was clastogenic in the in vivo rat micronucleus assay.

No carcinogenicity studies have been conducted with Eribulin.

A fertility study was not conducted with Eribulin, but based on non-clinical findings in repeated-dose studies where testicular toxicity was observed in both rats (hypocellularity of seminiferous epithelium with hypospermia/aspermia) and dogs, male fertility may be compromised by treatment with Eribulin. An embryofoetal development study in rat confirmed the developmental toxicity and teratogenic potential of Eribulin. Pregnant rats were treated with Eribulin Mesilate equivalent to 0.009, 0.027, 0.088 and 0.133 mg/kg Eribulin at gestation days 8, 10 and 12. Dose related increased number of resorptions and decreased foetal weight were observed at doses ≥ 0.088 mg/kg and increased incidence of malformations (absence of lower jaw, tongue, stomach and spleen) was recorded at 0.133 mg/kg.

6. Pharmaceutical particulars

6.1 List of excipients

Ethanol anhydrous 4.5% to 5.5%.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vials

5 years.

In-use shelf life

From 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  Eribulin Mesylate 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  Eribulin Mesylate (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.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions after first opening or dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

5 ml type I glass vial, with teflon-coated, butyl rubber stopper and flip-off aluminium over seal, containing 2 ml of solution.

The pack sizes are cartons of 1 or 6 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Eribulin Mesylate is a cytotoxic anticancer medicinal product and, as with other toxic compounds, caution should be exercised in its handling. The use of gloves, goggles, and protective clothing is recommended. If the skin comes into contact with the solution it should be washed immediately and thoroughly with soap and water. If it contacts mucous membranes, the membranes should be flushed thoroughly with water. Eribulin Mesylate should only be prepared and administered by personnel appropriately trained in handling of cytotoxic agents. Pregnant staff should not handle Eribulin Mesylate.

Using aseptic technique Eribulin Mesylate 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.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Manufactured in India By:
   TAJ PHARMACEUTICALS LIMITED
   at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
   ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).

Eribulin Mesylate Taj Pharma 0.44 mg/ml solution for injection

Package leaflet: Information for the user

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or nurse.
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

1. Eribulin Mesylate is and what it is used for
   2. What you need to know before you use Eribulin Mesylate
   3. How to use Eribulin Mesylate
   4. Possible side effects
   5. How to store Eribulin Mesylate
   6. Contents of the pack and other information
2. Eribulin Mesylate is and what it is used for

Eribulin Mesylate contains the active substance Eribulin and is an anti-cancer medicine which works by stopping the growth and spread of cancer cells.

It is used in adults for locally advanced or metastatic breast cancer (breast cancer that has spread beyond the original tumour) when at least one other therapy has been tried but has lost its effect.

It is also used in adults for advanced or metastatic liposarcoma (a type of cancer that arises from fat tissue) when previous therapy has been tried but has lost its effect.

2. What you need to know before you use Eribulin Mesylate

Do not use  Eribulin Mesylate:

• if you are allergic to Eribulin Mesylate or any of the other ingredients of this medicine (listed in section 6).
• if you are breast-feeding

Warnings and precautions

Talk to your doctor or nurse before using  Eribulin Mesylate:

• if you have liver problems
• if you have a fever or an infection
• if you experience numbness, tingling, prickling sensations, sensitivity to touch or muscle weakness
• if you have heart problems

If any of these affects you, tell your doctor who may wish to stop treatment or reduce the dose.

Children and adolescents

Eribulin Mesylate  is not recommended for children aged under 18 with paediatric sarcomas as it is not yet known how well it works in this age group.

Other medicines and  Eribulin Mesylate

Tell your doctor if you are using, have recently used or might use any other medicines.

Pregnancy, breast-feeding and fertility

Eribulin Mesylate may cause serious birth defects and should not be used if you are pregnant unless it is thought clearly necessary after carefully considering all the risk to you and the baby. It may also cause future permanent fertility problems in men if they take it and they should discuss this with their doctor before starting treatment. Women of childbearing age should use effective contraception during and up to 3 months after treatment with Eribulin Mesylate.

Eribulin Mesylate must not be used during breast-feeding because of the possibility of risk to the child.

Driving and using machines

Eribulin Mesylate may cause side effects such as tiredness (very common) and dizziness (common). Do not drive or use machines if you feel tired or dizzy.

Eribulin Mesylate contains ethanol (alcohol)

This medicine contains small amounts of ethanol (alcohol), less than 100 mg in a vial.

3. How to use Eribulin Mesylate

Eribulin Mesylate will be given to you by a doctor or nurse as an injection into a vein, over a period of 2 to 5 minutes. The dose you will receive is based on your body surface area (expressed in squared metres, or m²) which is calculated from your weight and height. The usual dose of Eribulin Mesylate is 1.23 mg/m², but this may be adjusted by your doctor based on your blood test results or other factors. To ensure that the whole dose of Eribulin Mesylate is given it is recommended that a saline solution is flushed into the vein after Eribulin Mesylate is given.

How often will you be given Eribulin Mesylate?

Eribulin Mesylate is usually given on Days 1 and 8 of every 21-day cycle. Your doctor will determine how many cycles of treatment you should receive. Depending on the results of your blood tests, the doctor may need to delay administration of the medicine until the blood tests return to normal. The doctor may also then decide to reduce the dose you are given.

If you have any further questions about the use of this medicine, ask your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you experience any of the following serious symptoms, stop taking Eribulin Mesylate and seek medical attention straightaway:

• Fever, with a racing heart beat, rapid shallow breathing, cold, pale, clammy or mottled skin and/or confusion. These may be signs of a condition called sepsis – a severe and serious reaction to an infection. Sepsis is uncommon (may affect up to 1 in 100 people) and can be life-threatening and may result in death.
• Any difficulty breathing, or swelling of your face, mouth, tongue or throat. These could be signs of an uncommon allergic reaction (may affect up to 1 in 100 people).
• Serious skin rashes with blistering of the skin, mouth, eyes and genitals. These may be signs of a condition called Stevens Johnson syndrome/toxic epidermal necrolysis. The frequency of this condition is not known but it can be life-threatening.

Other side effects:

Very common side effects (may affect more than 1 in 10 people) are:

• Decrease in the number of white blood cells or red blood cells
• Tiredness or weakness
• Nausea, vomiting, constipation, diarrhoea
• Numbness, tingling or prickling sensations
• Fever
• Loss of appetite, weight loss
• Difficulty breathing, cough
• Pain in the joints, muscles and back
• Headache
• Hair loss

Common side effects (may affect up to 1 in 10 people) are:

• Decrease in the number of platelets (which may result in bruising or taking longer to stop bleeding)
• Infection with fever, pneumonia, chills
• Fast heart rate, flushing
• Vertigo, dizziness
• Increased production of tears, conjunctivitis (redness and soreness of the surface of the eye), nosebleed
• Dehydration, dry mouth, cold sores, oral thrush, indigestion, heartburn, abdominal pain or swelling
• Swelling of soft tissues, pains (in particular chest, back and bone pain), muscle spasm or weakness
• Mouth, respiratory and urinary tract infections, painful urination
• Sore throat, sore or runny nose, flu-like symptoms, throat pain
• Liver function test abnormalities, altered level of sugar, bilirubin, phosphates, potassium, magnesium or calcium in the blood
• Inability to sleep, depression, changed sense of taste
• Rash, itching, nail problems, dry or red skin
• Excessive sweating (including night sweats)
• Ringing in the ears
• Blood clots in the lungs
• Shingles
• Swelling of the skin and numbness of the hands and feet

Uncommon side effects (may affect up to 1 in 100 people) are:

• Blood clots
• Abnormal liver function tests (hepatoxicity)
• Kidney failure, blood or protein in the urine
• Widespread inflammation of the lungs which may lead to scarring
• Inflammation of the pancreas
• Mouth ulcers

Rare side effects (may affect up to 1 in 1000 people) are:

• A serious disorder of blood clotting resulting in the widespread formation of blood clots and internal bleeding.

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet.

5. How to store Eribulin Mesylate

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and the vial after EXP. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What  Eribulin Mesylate contains

• The active substance is Eribulin. Each 2 ml vial contains Eribulin Mesilate equivalent to 0.88 mg Eribulin.
• The other ingredients are ethanol and water for injections, with hydrochloric acid and sodium hydroxide possibly present in very small amounts.

 6.1 Eribulin Mesylate looks like and contents of the pack

Eribulin Mesylate is a clear, colourless aqueous solution for injection provided in glass vials containing 2 ml of solution.

7. Manufactured in India By:
   TAJ PHARMACEUTICALS LIMITED
   at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
   ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).