Eribulin

Eribulin mesilate is a microtubule dynamics inhibitor of the halichondrin class of anti-cancer medicines. It is a structurally simplified synthetic analogue of halichondrin B, a natural product isolated from the marine sponge Halichondria okadai. It stops cancer cells from completing mitosis by interfering with the microtubules of the mitotic spindle.

Mechanism of Action

• Microtubule growth inhibition: eribulin inhibits the growth phase of microtubules without affecting the shortening phase, and it sequesters tubulin into non-productive aggregates.
• Mitotic block: this tubulin-based antimitotic mechanism causes a G2/M cell-cycle block and disrupts the mitotic spindles. After prolonged and irreversible mitotic blockage the cell dies by apoptosis.

Pharmacokinetics

• Administration: given intravenously, so there is no absorption phase.
• Distribution: a rapid distribution phase is followed by a prolonged elimination phase. The volume of distribution is large (means of 43 to 114 L/m²). Eribulin is weakly bound to plasma proteins (49% to 65% at 100–1,000 ng/mL).
• Metabolism: unchanged eribulin is the main circulating species; metabolite concentrations were below 0.6% of the parent compound, so there are no major human metabolites. CYP3A4 metabolises eribulin only negligibly in vitro.
• Elimination: low clearance (means of 1.16 to 2.42 L/h/m²) and a mean terminal half-life of about 40 hours. No significant accumulation occurs with weekly administration, and the pharmacokinetics are not dose- or time-dependent between 0.22 and 3.53 mg/m². Elimination is mainly by biliary excretion, through a transport protein that is not yet identified. After a radiolabelled dose about 82% was recovered in faeces and 9% in urine, mostly as unchanged eribulin, so renal clearance is not an important route.
• Special populations: in liver metastases, exposure rose 1.8-fold in mild (Child-Pugh A) and 3-fold in moderate (Child-Pugh B) hepatic impairment compared with normal liver function; reduced doses of 0.97 and 0.62 mg/m² respectively gave somewhat higher exposure than the standard dose in patients with normal liver function. Severe impairment (Child-Pugh C) was not studied. Patients with moderately or severely impaired renal function (creatinine clearance below 50 mL/min) may have increased exposure.

• Breast cancer: adults with locally advanced or metastatic breast cancer who have progressed after at least one chemotherapeutic regimen for advanced disease. Prior therapy should have included an anthracycline and a taxane, in the adjuvant or metastatic setting, unless the patient was not suitable for these treatments.
• Liposarcoma: adults with unresectable liposarcoma who have received prior anthracycline-containing therapy (unless unsuitable) for advanced or metastatic disease.

• Hypersensitivity to eribulin or to any of the excipients.
• Breastfeeding.

The most commonly reported reactions are bone marrow suppression, shown as neutropenia, leucopenia, anaemia and thrombocytopenia with associated infections; new or worsening peripheral neuropathy; and gastrointestinal effects such as anorexia, nausea, vomiting, diarrhoea, constipation and stomatitis. Other reported reactions include fatigue, hair loss, raised liver enzymes, sepsis and musculoskeletal pain syndrome. The frequencies below come from breast cancer and soft tissue sarcoma patients given the recommended dose, and the safety profiles in the two groups were generally similar.

Very common (≥1/10): blood and lymphatic system: neutropenia (53.6%), leucopenia (27.9%), anaemia (21.8%); metabolism and nutrition: decreased appetite (22.5%); nervous system: peripheral neuropathy (35.9%), headache (17.5%); respiratory: dyspnoea (15.2%), cough (15.0%); gastrointestinal: nausea (35.7%), constipation (22.3%), diarrhoea (18.7%), vomiting (18.1%); skin: alopecia; musculoskeletal: arthralgia and myalgia (20.4%), back pain (12.8%), pain in extremity (10.0%); general: fatigue or asthenia (53.2%), pyrexia (21.8%); investigations: weight loss (11.4%).

Common (≥1/100 to <1/10): infections: urinary tract infection (8.5%), pneumonia (1.6%), oral candidiasis, oral herpes, upper respiratory tract infection, nasopharyngitis, rhinitis, herpes zoster; blood: lymphopenia (5.7%), febrile neutropenia (4.5%), thrombocytopenia (4.2%); metabolism: hypokalaemia (6.8%), hypomagnesaemia (2.8%), dehydration (2.8%), hyperglycaemia, hypophosphataemia, hypocalcaemia; psychiatric: insomnia, depression; nervous system: dysgeusia, dizziness (9.0%), hypoaesthesia, lethargy, neurotoxicity; eye: increased lacrimation (5.8%), conjunctivitis; ear: vertigo, tinnitus; cardiac: tachycardia; vascular: hot flush, pulmonary embolism (1.3%); respiratory: oropharyngeal pain, epistaxis, rhinorrhoea; gastrointestinal: abdominal pain, stomatitis (11.1%), dry mouth, dyspepsia (6.5%), gastro-oesophageal reflux disease, abdominal distension; liver: raised AST (7.7%), raised ALT (7.6%), raised gamma-glutamyltransferase (1.7%), hyperbilirubinaemia (1.4%); skin: rash (4.9%), pruritus (3.9%), nail disorder, night sweats, dry skin, erythema, hyperhidrosis, palmar-plantar erythrodysaesthesia (1.0%); musculoskeletal: bone pain (6.7%), muscle spasms (5.3%), musculoskeletal pain, musculoskeletal chest pain, muscular weakness; urinary: dysuria; general: mucosal inflammation (6.4%), peripheral oedema, pain, chills, chest pain, influenza-like illness.

Uncommon (≥1/1,000 to <1/100): sepsis (0.5%), neutropenic sepsis (0.2%), septic shock (0.2%), deep vein thrombosis, interstitial lung disease (0.2%), mouth ulceration, pancreatitis, hepatotoxicity (0.8%), angioedema, haematuria, proteinuria, renal failure.

Rare (≥1/10,000 to <1/1,000): disseminated intravascular coagulation (from spontaneous reports).

Not known: Stevens-Johnson syndrome and toxic epidermal necrolysis (from spontaneous reports).

Important serious reactions are severe neutropenia (Grade 3 or 4 in 46.0% of patients), febrile neutropenia, sepsis and septic shock, including fatal cases, and peripheral neuropathy (Grade 3 or 4 in 7.3%). Pulmonary embolism, pancreatitis, hepatotoxicity, interstitial lung disease and severe skin reactions have also been reported.

Eribulin is eliminated mainly (up to 70%) by biliary excretion. It is not a substrate of BCRP, OAT1, OAT3, OATP1B1, OATP1B3, MRP2, MRP4 or the bile salt export pump.

• CYP3A4 and P-gp inhibitors and inducers: no interactions are expected. Eribulin exposure was unaffected by ketoconazole (a CYP3A4 and P-glycoprotein inhibitor) and by rifampicin (a CYP3A4 inducer).
• CYP3A4 substrates with a narrow therapeutic window: eribulin is a mild CYP3A4 inhibitor in vitro and there are no in vivo data. Caution and monitoring for adverse events are advised with medicines that have a narrow therapeutic window and are cleared mainly by CYP3A4, such as alfentanil, fentanyl, ciclosporin, ergotamine, pimozide, quinidine, sirolimus and tacrolimus.
• Medicines that prolong the QT interval: ECG monitoring is recommended when eribulin is started in patients taking such medicines, including class Ia and III antiarrhythmics (see Special Instructions).
• Other enzymes and transporters: at relevant clinical concentrations eribulin does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 2E1, nor the transporters BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1 and OATP1B3.

Eribulin must be prescribed only by a qualified physician experienced in anti-cancer therapy and given only by an appropriately qualified healthcare professional. Nausea and vomiting can occur, and antiemetic prophylaxis including corticosteroids should be considered.

Recommended Dose

• 1.23 mg/m² of eribulin, given intravenously over 2 to 5 minutes on Days 1 and 8 of every 21-day cycle.
• In the EU the dose is expressed as eribulin (the base), not as the salt eribulin mesilate. The individual dose is calculated from the 0.44 mg/mL ready-to-use solution. Some publications and regions outside the EU express the dose as the salt form, so figures quoted there are not directly comparable.

Method of Administration

• The dose may be diluted in up to 100 mL of 0.9% sodium chloride solution; it must not be diluted in 5% glucose.
• Good peripheral venous access or a patent central line should be ensured. There is no evidence that eribulin is a vesicant or an irritant; in the event of extravasation, treatment is symptomatic.
• Handling follows the rules for cytotoxic medicines (see section 6.6 of the SmPC).

Dose Delays

Day 1 or Day 8 treatment should be delayed if any of the following is present:

• absolute neutrophil count (ANC) below 1 ×10⁹/L;
• platelets below 75 ×10⁹/L;
• Grade 3 or 4 non-haematological toxicity.

Dose Reductions

• Reduce to 0.97 mg/m² after: ANC below 0.5 ×10⁹/L lasting more than 7 days; ANC below 1 ×10⁹/L with fever or infection; platelets below 25 ×10⁹/L; platelets below 50 ×10⁹/L with haemorrhage or needing a blood or platelet transfusion; or any Grade 3 or 4 non-haematological reaction in the previous cycle.
• Reduce to 0.62 mg/m² if any of these reactions recurs despite the reduction to 0.97 mg/m².
• Consider discontinuation if they recur despite the reduction to 0.62 mg/m².
• The dose should not be increased again once it has been reduced.

Special Populations

• Hepatic impairment due to liver metastases: mild (Child-Pugh A) 0.97 mg/m², moderate (Child-Pugh B) 0.62 mg/m², each over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. Severe impairment (Child-Pugh C) has not been studied and a more marked dose reduction is expected to be needed.
• Hepatic impairment due to cirrhosis: not studied. The doses above may be used in mild and moderate impairment, but close monitoring is advised because the dose may need readjustment.
• Renal impairment: patients with creatinine clearance below 50 mL/min may have increased exposure and may need a lower dose. Caution and close safety monitoring are advised in all renal impairment.
• Elderly: no specific dose adjustment based on age.
• Children and adolescents: there is no relevant use in the paediatric population for breast cancer or for soft tissue sarcoma.

Haematology

Myelosuppression is dose-dependent and appears mainly as neutropenia. A complete blood count is needed before every dose, and treatment should be started only if the ANC is at least 1.5 ×10⁹/L and platelets are above 100 ×10⁹/L. Febrile neutropenia occurred in under 5% of patients. Patients with ALT or AST above 3 times the upper limit of normal had more Grade 4 neutropenia and febrile neutropenia, and so did patients with bilirubin above 1.5 times the upper limit (data are limited). Fatal febrile neutropenia, neutropenic sepsis, sepsis and septic shock have been reported. Severe neutropenia may be managed with granulocyte colony-stimulating factor (G-CSF) or an equivalent at the physician’s discretion.

Peripheral Neuropathy

Patients are monitored closely for signs of motor and sensory neuropathy. Severe peripheral neurotoxicity requires a delay or a dose reduction. Patients with pre-existing neuropathy worse than Grade 2 were excluded from the trials; those with Grade 1 or 2 neuropathy were no more likely to develop new or worsening symptoms.

QT Prolongation

In a small uncontrolled ECG study (26 patients) QT prolongation was seen on Day 8 but not on Day 1, independent of eribulin concentration. ECG monitoring is recommended when treatment starts in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities or concomitant QT-prolonging medicines, including class Ia and III antiarrhythmics. Hypokalaemia, hypocalcaemia and hypomagnesaemia should be corrected before starting and monitored periodically. Eribulin should be avoided in congenital long QT syndrome.

Pregnancy, Contraception, Breastfeeding and Fertility

• Pregnancy: no data in pregnant women. Eribulin is embryotoxic, foetotoxic and teratogenic in rats, and it should not be used in pregnancy unless clearly necessary after careful consideration of the mother’s needs and the risk to the foetus.
• Contraception in women: women who can become pregnant must avoid pregnancy and use highly effective contraception during treatment and for 7 months afterwards.
• Contraception in men: men with partners who can become pregnant should not father a child during treatment and must use effective contraception during treatment and for 4 months afterwards.
• Breastfeeding: it is unknown whether eribulin or its metabolites pass into breast milk. A risk to the infant cannot be excluded, and eribulin must not be used during breastfeeding.
• Fertility: testicular toxicity was seen in rats and dogs. Men should seek advice on sperm conservation before treatment because of the possibility of irreversible infertility.

Alcohol Content

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

Effect on Driving

Tiredness and dizziness can have a minor to moderate influence on the ability to drive or use machines. Patients who feel tired or dizzy should not drive or use machines.

Halaven needs no special storage conditions and no cold chain. The solution (2 mL) is supplied in 5 mL glass vials, in cartons of 1 or 6 (not all pack sizes may be marketed). Once the vial has been opened or the solution diluted, use it immediately; if it is not, in-use times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions. Chemical and physical stability has been shown for the undiluted solution in a syringe for up to 4 hours at 15–25 °C under ambient lighting or up to 24 hours at 2–8 °C, and for the diluted solution (0.018 to 0.18 mg/mL eribulin in 0.9% sodium chloride) for up to 72 hours at 2–8 °C.

Unopened vials: 5 years. In-use stability is described under Storage Conditions.

Prescription only (Rx), on the prescription of a physician experienced in anti-cancer therapy. Eribulin is an intravenous cytotoxic injection given by a qualified healthcare professional, so it is supplied to the hospital or clinic that administers it. It does not need cold-chain transport.