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Drug Details

Halaven

Presentation
One ml contains 0.44 mg of eribulin (as mesylate) Each 2 ml vial contains 0.88 mg of eribulin (as mesylate)
Description
Solution for injection. Clear, colourless aqueous solution.
Indications
monotherapy 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 (see section 5.1). Prior therapy should have included an anthracycline and a taxane unless patients were not suitable for these treatments

Adult Dosage

Halaven should be administered in units specialised in the administration of cytotoxic chemotherapy and only 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(equivalent to 1.4 mg/m² eribulin mesylate) which should be administered intravenously over 2 to 5 minutes on Days 1 and 8 of every 21-day cycle.

Patients may experience nausea or vomiting. Antiemetic prophylaxis including corticosteroids should be considered.

Dose delays during therapy

The administration of Halaven should be delayed on Day 1 or Day 8 for any of the following:

− Absolute neutrophil count (ANC) < 1 x 10⁹/l

− Platelets < 75 x 10⁹/l

− Grade 3 or 4 non-hematological toxicities.

Dose reduction during therapy

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

Dose reduction recommendations

Adverse reaction after previous Halaven administration	Recommended dose
Haematological:
ANC < 0.5 x 10⁹/l lasting more than 7 days	0.97 mg/m²
ANC < 1 x 10⁹/l neutropenia complicated by fever or infection
Platelets < 25 x 10⁹/l thrombocytopenia
Platelets < 50 x 10⁹/l thrombocytopenia complicated by haemorrhage or requiring blood or platelet transfusion
Non-haematological:
Any Grade 3 or 4 in the previous cycle
Reoccurrence of any haematological or non-haematological adverse reactions as specified above
Despite reduction to 0.97 mg/m²	0.62 mg/m²
Despite reduction to 0.62 mg/m²	Consider discontinuation

Do not re-escalate the eribulin dose 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

Patients with severely impaired renal function (creatinine clearance <40 ml/min) may need a reduction of the dose (See section 5.2). The optimal dose for this patient groups remains to be established. Caution and close safety monitoring as advised. No specific dose adjustments are recommended for patients with mild to moderate renal impairment.

Elderly patients

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

Paediatric patients

There is no relevant use of Halaven in children and adolescents in the indication of breast cancer.

Method of administration

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 mesylate is a vesicant or an irritant. In the event of extravasation, treatment should be symptomatic.

Contra Indications

Hypersensitivity to the active substance or to any of the excipients

- Breast feeding

Special Precautions

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 breast cancer patients treated with eribulin. Patients experiencing febrile neutropenia, severe neutropenia or thrombocytopenia, should be treated according to the recommendations in section 4.2.

Patients with 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.

Severe neutropenia may be managed by the use of 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, medicinal products known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Hypokalemia or hypomagnesemia should be corrected prior to initiating Halaven and these electrolytes should be monitored periodically during therapy. Eribulin should be avoided in patients with congenital long QT syndrome.

Use in combination with anti-HER2 therapy

There is no experience of using eribulin in combination with anti-HER2 therapy in clinical trials.

Excipients

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

Haematology

Severe neutropenia may be managed by the use of 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)

QT prolongation

Use in combination with anti-HER2 therapy

There is no experience of using eribulin in combination with anti-HER2 therapy in clinical trials.

Excipients

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

Interactions
Eribulin is mainly (up to 70%) eliminated through biliary excretion. The transport protein involved in this process is unknown. Complete inhibition of the transport could in theory give rise to a more than 3-fold increase in plasma concentrations. It is not recommended to use substances which are inhibitors of hepatic transport proteins such as organic anion-transporting proteins (OATPs), P-glycoprotein (Pgp), multidrug resistant proteins (MRPs) etc concomitantly with eribulin. Inhibitors of such transporters include but are not limited to: cyclosporine, ritonavir, saquinavir, lopinavir and certain other protease inhibitors, efavirenz, emtricitabine, verapamil, clarithromycin, quinine, quinidine, disopyramide etc.

Concomitant treatment with enzyme inducing substances such as rifampicin, carbamazepine, phenytoin, St John´s wort (Hypericum perforatum) is not recommended as these drugs are likely to give rise to markedly reduced plasma concentrations of eribulin.

No drug-drug interactions are expected with CYP3A4 inhibitors unless they are potent inhibitors of Pgp. Eribulin exposure (AUC and C_max) was unaffected by ketoconazole, a CYP3A4 inhibitor.

Effects of eribulin on the pharmacokinetics of other drugs

Eribulin may inhibit the important drug metabolising enzyme CYP3A4. This is indicated by in vitro data and no in vivo data is available. Concomitant use with substances that are mainly metabolised by CYP3A4 should be made with caution and it is recommended that the patient is closely monitored for adverse effects due to increased plasma concentrations of the concomitantly used substance. If the substance has a narrow therapeutic range, concomitant use should be avoided.

Eribulin does not inhibit the CYP enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 2E1 at relevant clinical concentrations.

Adverse Drug Reactions

The most commonly reported adverse reactions to eribulin are shown in the table below.

The following table shows the incidence rates of adverse reactions observed in 827 breast cancer patients who received the recommended dose in two Phase 2 and one Phase 3 study. 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), 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. Actual frequencies are shown where Grade 3 or 4 reactions occurred with a frequency of 1%.

System Organ Class	Adverse Reactions – all Grades		Grade 3 and 4 Reactions 1% Frequency %
	Very Common (Frequency %)	Common (Frequency %)	Grade 3 and 4 Reactions 1% Frequency %
Infections and infestations		Urinary tract infection Oral candidiasis Upper respiratory tract infection Nasopharyngitis Rhinitis
Blood and lymphatic disorders	Neutropenia (54.5%) Leukopenia (22.1%) Anaemia (20.3%)	Febrile neutropenia (4.7%) Thrombocytopenia Lymphopenia	Neutropenia 48.3% Leukopenia 14% Febrile neutropenia 4.6%^a Anaemia 1.4%
Metabolism and nutrition disorders	Decreased appetite	Hypokalaemia Hypomagnesaemia Dehydration Hyperglycaemia Hypophosphataemia
Psychiatric disorders		Insomnia Depression
Nervous system disorders	Peripheral neuropathy ^b (32.0%) Headache	Dysgeusia Dizziness Hypoaesthesia Lethargy Neurotoxicity	Peripheral neuropathy^b 6.9%
Eye disorders		Lacrimation increased Conjunctivitis
Ear and Labyrinth Disorders		Vertigo
Cardiac disorders		Tachycardia
Vascular disorders		Hot flush
Respiratory, thoracic and mediastinal disorders		Dyspnoea Cough Oropharyngeal pain Epistaxis Rhinorrhoea
Gastrointestinal disorders	Nausea (35.1%) Constipation Diarrhoea Vomiting	Abdominal pain Stomatitis Dry mouth Dyspepsia Gastrooesophageal reflux disease Mouth ulceration Abdominal distension	Nausea 1.1%^c
Hepatobiliary disorders		Alanine aminotransferase increased (3.0%) Aspartate aminotransferase increased	Alanine aminotransferase increased 1.1%^c
Skin and subcutaneous tissue disorders	Alopecia	Rash Pruritus Nail disorder Night sweats Palmar plantar erythrodysaesthesia Dry skin Erythema Hyperhidrosis
Musculoskeletal and connective tissue disorders	Arthralgia and Myalgia	Pain in extremity Muscle spasms Musculoskeletal pain and Musculoskeletal chest pain Muscular weakness Bone pain Back pain
General disorders and administration site conditions	Fatigue/Asthenia (52.8%) Pyrexia	Mucosal Inflammation (9.8%) Peripheral oedema Pain Chills Influenza like illness Chest Pain	Fatigue/Asthenia 8.4% Mucosal Inflammation 1.3%^c
Investigations		Weight decreased

^aIncludes 1 Grade 5

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

^cNo Grade 4

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, Oral herpes, Herpes zoster

Ear and labyrinth disorders: Tinnitus

Vascular disorders: Deep vein thrombosis, pulmonary embolism

Respiratory, thoracic and mediastinal disorders: Interstitial lung disease

Hepatobiliary disorders: Hyperbilirubinaemia

Skin and subcutaneous tissue disorder: Angioedema

Renal disorders: Dysuria, Haematuria, Proteinuria, Renal failure

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.

Severe neutropenia may be managed by the use of G-CSF or equivalent at the physician's discretion in accordance with relevant guidelines. 18% of breast cancer patients treated in a phase 3 study with eribulin received G-CSF.

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

Peripheral neuropathy

In the 827 breast cancer patients the most common adverse reaction resulting in discontinuation of treatment with eribulin was peripheral neuropathy (4%). The median time to Grade 2 peripheral neuropathy was 85 days (post 4 cycles).

Development of Grade 3 or 4 peripheral neuropathy occurred in 7% of eribulin treated breast cancer patients. In clinical trials, patients with pre-existing neuropathy were as likely to develop new or worsening symptoms as those who entered the study without the condition.

In patients with pre-existing Grade 1 or 2 peripheral neuropathy the frequency of treatment-emergent Grade 3 peripheral neuropathy was 10%.

Special populations

Elderly population

In studies of 1,222 patients treated with eribulin, 244 patients (20.0%) were > 65 - 75 years of age and 66 patients (5.4%) were > 75 years of age. Among the 827 of these patients who received the recommended dose of eribulin in the Phase 2/3 breast cancer studies, 121 patients (14.6%) were > 65 - 75 years of age and 17 patients (2.1%) were > 75 years of age. The safety profile of eribulin in elderly patients (> 65 years of age) was similar to that of patients 65 years of age. 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).