Eribulin

Registered South African indications

• Locally advanced or metastatic breast cancer
  - In patients who have progressed after at least one chemotherapeutic regimen for advanced disease. 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
• Unresectable liposarcoma
  - In patients who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding

South African recommendations

Caution in the following patient groups

• Moderate to severe renal impairment (CrCl<50ml/min)
• Hepatic impairment

Haematology

• Myelosuppression and neutropenia: Dose-dependent neutropenia is common; monitor blood counts before each eribulin dose and only initiate treatment if ANC ≥1.5 x 10⁹/l and platelets >100 x 10⁹/l
• Fatal cases of febrile neutropenia, septic shock, and sepsis have occurred; severe cases may require G-CSF support or dosage adjustments
• Hepatic impairment risk: Patients with elevated transaminases >3 x upper limit of normal (ULN) or bilirubin >1.5 x ULN face a higher risk of Grade 4 neutropenia and febrile neutropenia

Peripheral neuropathy

• Peripheral neurotoxicity: Closely monitor for signs of motor and sensory neuropathy; development of severe symptoms requires dose delays or reductions of eribulin
• Patients with pre-existing Grade 1 or 2 neuropathy should be monitored, though they have not shown a higher likelihood of worsening symptoms compared to those without the condition

QT prolongation

• ECG monitoring is recommended in patients with congestive heart failure, bradydysrhythmias, or electrolyte imbalances due to observed QT prolongation with eribulin
• Avoid concurrent use of medicines known to prolong the QT interval, such as Class Ia and III antidysrhythmics
• Correct hypokalaemia or hypomagnesaemia prior to initiating treatment and monitor these electrolytes periodically during therapy
• Eribulin should be avoided in patients with congenital long QT syndrome

Effects on ability to drive and use machines

• Eribulin may cause tiredness and dizziness; patients should be advised to avoid driving or operating machinery while receiving treatment

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Locally advanced or metastatic breast cancer
- In patients who have progressed after at least one chemotherapeutic regimen for advanced disease. 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
Unresectable liposarcoma
- In patients who have received prior anthracycline containing therapy (unless unsuitable) for advanced or metastatic disease

Eribulin should be administered in units specialised in the administration of cytotoxic chemotherapy and only under the supervision of a qualified medical practitioner experienced in the appropriate use of cytotoxic medicines

• IV: 1.23mg/m², given over 2-5mins on day 1 and 8 of every 21 days

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IMPORTANT
PLEASE NOTE: 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 0.44mg/ml eribulin and the dose recommendation of 1.23mg/m². The dose reduction recommendation 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 US and Switzerland, the recommended dose is based on the salt form (eribulin mesilate). Patients may experience nausea or vomiting. Anti-emetic prophylaxis including corticosteroids should be considered.

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Dose delays during therapy
The administration of eribulin 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-haematological toxicities

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For dose reduction during therapy and method of administration, see Additional Prescriber Points

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Do not re-escalate the eribulin dose after it has been reduced

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• Eribulin is contraindicated in pregnancy
• There are no data from the use of eribulin in pregnant women. Eribulin is embryotoxic, foetotoxic, and teratogenic in rats. Eribulin should not be used during pregnancy

Women of childbearing age

• If you could become pregnant, you should use appropriate contraception methods during treatment and for 7 months following the last dose of eribulin
• Men receiving eribulin are advised to use appropriate contraception methods during treatment and for 4 months following the last dose of eribulin. It is recommended that those who wish to become fathers in the future discuss the possibility of freezing of their sperm prior to treatment

Breastfeeding

South African recommendations

• Contraindicated
• Eribulin is contraindicated during lactation
• There is no information on the excretion of eribulin or its metabolites in human or animal breast milk. Mothers on eribulin must not breastfeed their infants

Fertility

South African recommendations

• Testicular toxicity has been observed in rats and dogs
• Male patients should seek advice on the conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with eribulin

South African recommendations

• Mild (CrCl ≥50ml/min): No dose adjustment recommended
• Moderate (CrCl 30-50ml/min): Caution; dose adjustment recommended
  Patients with moderately impaired renal function will have increased eribulin exposure
  Recommended dosage: IV: 1.1mg/m², admin over 2-5mins on days 1 and 8 of a 21-day cycle
• Severe (CrCl<30ml/min): Caution; no information available
  Patients with severely impaired renal function will have increased eribulin exposure
  The safety of eribulin was not studied in patients with severe renal impairment (CrCl<30ml/min). For all patients with renal impairment, caution and close safety monitoring is advised

South African recommendations

Impaired liver function due to metastases

• Mild (Child-Pugh A): Caution; dose adjustment recommended
  Recommended dosage: IV: 0.97mg/m², admin. over 2-5mins on days 1 and 8 of a 21-day cycle
• Moderate (Child- Pugh B): Caution; dose adjustment recommended
  Recommended dosage: IV: 0.62mg/m², admin. over 2-5mins on days 1 and 8 of a 21-day cycle
• Severe (Child-Pugh C): Caution; no information available
  Severe renal impairment 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

• Caution; no information available
  This patient group has not been studied. The doses given above may be used in mild and moderate impairment, but close monitoring is advised as the doses may need readjustment

South African recommendations

• No dose adjustment recommended

Central Nervous System Disorders

• Insomnia
• Depression
• Peripheral neuropathy
  - Peripheral motor neuropathy
  - Polyneuropathy
  - Paraesthesia
  - Peripheral sensory neuropathy
  - Peripheral sensorimotor neuropathy
  - Demyelinating polyneuropathy
• Headache
• Dizziness
• Hypoaesthesia
• Lethargy
• Neurotoxicity
• Fatigue

Cardiovascular Disorders

• Tachycardia
• Hot flush
• Pulmonary embolism
• Deep vein thrombosis
• Chest pain

Respiratory Disorders

• Pneumonia
• Upper respiratory tract infection
• Nasopharyngitis
• Rhinitis
• Dyspnoea
• Cough
• Oropharyngeal pain
• Epistaxis
• Rhinorrhoea
• Interstitial lung disease

Gastrointestinal Disorders

• Oral candidiasis
• Oral herpes
• Nausea and vomiting
• Constipation
• Diarrhoea
• Abdominal pain
• Stomatitis
• Dry mouth
• Dyspepsia
• Gastroesophageal reflux disease
• Abdominal distension
• Mouth ulceration

Hepatobiliary Disorders

• Increased aspartate aminotransferase
• Increased alanine aminotransferase
• Increased gamma glutamyl transferase
• Hyperbilirubinaemia
• Hepatotoxicity

Genitourinary Disorders

• Urinary tract infection
• Dysuria
• Haematuria
• Proteinuria
• Renal failure

Endocrine and Metabolic Disorders

• Decreased appetite
• Hypokalaemia
• Hypomagnesaemia
• Dehydration
• Hyperglycaemia
• Hypophosphataemia
• Hypocalcaemia
• Decreased weight
• Pancreatitis

Musculoskeletal Disorders

• Myalgia
• Back pain
• Pain in extremity
• Bone pain
• Muscle spasms
• Musculoskeletal pain
• Musculoskeletal chest pain
• Muscular weakness
• Arthralgia

Skin and Subcutaneous Tissue Disorders

• Alopecia
• Rash
• Pruritus
• Nail disorder
• Night sweats
• Dry skin
• Erythema
• Hyperhidrosis
• Palmar plantar erythrodysaesthesia
• Angioedema
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Mucosal inflammation

Immune, Blood and Lymphatic System Disorders

• Herpes zoster
• Sepsis
• Neutropenic sepsis
• Septic shock
• Neutropenia
• Leukopenia
• Anaemia
• Lymphopenia
• Febrile neutropenia
• Thrombocytopenia
• Disseminated intravascular coagulation
• Fever
• Influenza like illness
• Chills
• Peripheral oedema

Sensory Disorders

• Increased lacrimation
• Conjunctivitis
• Vertigo
• Tinnitus
• Dysgeusia

• QT prolonging agents
• Class Ia and III antiarrhythmics
• Agents with a narrow therapeutic window that are eliminated mainly via CYP3A4-mediated metabolism
• Alfentanil
• Cyclosporine
• Ergotamine
• Fentanyl
• Pimozide
• Quinidine
• Sirolimus
• Tacrolimus

• Full blood count with differential
• Renal function
• Hepatic function
• Electrolytes

Specific cases may require

• ECG

Dose reduction during therapy

Dose reduction recommendations for retreatment are shown in the following table

Adverse reaction after previous eribulin administration	Recommended dose of eribulin
Haematological
ANC <0.5 x 109/l lasting more than 7 days	0.97mg/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 0.97mg/m2	0.62mg/m2
Despite reduction to 0.62mg/m2	Consider discontinuation

Method of administration

• Eribulin is for intravenous use
• The dose may be diluted in up to 100ml of sodium chloride 9mg/ml (0.9% NaCl) solution for injection
• It should not be diluted in glucose 5% infusion solution. In the absence of compatibility studies eribulin must not be mixed with other medicines except sodium chloride 9mg/ml (0.9% NaCl) solution for injection
• Good peripheral venous access or a patent central line should be ensured prior to administration
• There is no evidence that eribulin is a vesicant or an irritant. In the event of extravasation, treatment should be symptomatic
• Following administration, it is recommended that the intravenous line be flushed with sodium chloride 9mg/ml (0.9% NaCl) solution for injection to ensure administration of the complete dose
• Eribulin is a cytotoxic anticancer medicine and 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 eribulin solution, the skin should be washed immediately and thoroughly with soap and water
• If the eribulin solution comes into contact with mucous membranes, the membranes should be flushed thoroughly with water
• Eribulin should only be prepared and administered by personnel appropriately trained in handling of cytotoxic medicines. Pregnant staff should not handle eribulin
• Discard any unused portion of the vial

Eribulin mesilate is a synthetic analogue of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai that inhibits tubulin formation and mitotic spindle function, leading to phase G2/M cell-cycle arrest. 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.

Injection (per 2ml) 0.88mg

• Halaven (Equity) originator