What Is Eribulin (Halaven)? FDA Approval, Licensing in Turkey, and Reimbursement Status

• FDA-Approved: Yes (first approval date: November 15, 2010)
• Product Name: Halaven
• Active Ingredient Name: Eribulin mesylate
• Method of Administration: Intravenous infusion
• Class: Microtubule inhibitor
• Category: Antineoplastic agent
• Manufacturer: Eisai
• Distribution in Turkey: Not licensed in Turkey. A brief explanation of how it can be obtained through TEB (Turkish Pharmacists' Association) is provided below.
• Approved Cancers:
  • Metastatic breast cancer: In patients with metastatic disease who have previously received at least two chemotherapy regimens and have not benefited from regimens containing an anthracycline or a taxane.
  • Advanced or metastatic liposarcoma: In patients who have been treated with an anthracycline-containing regimen and experienced disease progression.

What Is Eribulin (Halaven)?

Halaven, containing the active ingredient eribulin mesylate, is an intravenous antimicrotubule agent used to treat metastatic breast cancer and advanced/metastatic liposarcoma. It aims to slow tumor growth, particularly in patients previously treated with chemotherapy who do not respond to anthracycline- or taxane-based treatments.

What Is an Antimicrotubule Agent?

Antimicrotubule agents are drugs that disrupt the dynamics of cytoskeletal structures called microtubules during cell division. By inhibiting microtubule function, they stop cancer cells from dividing and multiplying. These agents are particularly effective during the G2-M phase of the cell cycle.

How Does It Work?

Eribulin is a synthetic analog of halichondrin B, a substance derived from the marine sponge Halichondria okadai. It exerts antitumor effects through the following mechanisms:

• Inhibition of Microtubule Growth: By disrupting microtubule dynamics, eribulin causes cell-cycle arrest in the G2-M phase and prevents cancer cells from dividing.
• No Effect on Microtubule Shortening: Eribulin inhibits only microtubule growth without affecting shortening. This gives it a mechanism distinct from that of other antimicrotubule agents.
• Inhibition of Angiogenesis: By inhibiting the development of blood vessels within the tumor, it restricts the tumor's access to oxygen and nutrients.
• Activity in Taxane-Resistant Cell Lines: Eribulin retains its activity in various tumor cell lines resistant to taxanes.

FDA (United States Food and Drug Administration) Approval History

• November 15, 2010: The FDA approved eribulin mesylate (Halaven) for use in patients with advanced metastatic breast cancer who had previously received at least two chemotherapy regimens.
• January 28, 2016: The FDA approved Halaven for patients with unresectable or metastatic liposarcoma who had been treated with an anthracycline-containing regimen.

Licensing in Turkey

Halaven, containing the active ingredient eribulin mesylate, has not been licensed by the Turkish Ministry of Health.

Is Halaven Reimbursed?

Halaven, containing eribulin mesylate, can be brought into Turkey with authorization for the use of medicines from abroad, as a drug not licensed by the Turkish Ministry of Health. This process is conducted through the Turkish Pharmacists' Association (TEB).

Process for Obtaining Medicines from Abroad:

For patients who need treatment, the treating medical oncologist must request authorization from the Turkish Ministry of Health for the use of the medicine from abroad.

After authorization is obtained, Halaven can be procured from abroad through the Turkish Pharmacists' Association (TEB).

This is an official process intended to facilitate and accelerate patients' access to treatment.

If eribulin is not covered by SGK (Social Security Institution), the patient may need to pay for the medicine themselves.

Price: A vial of Halaven costs 353.47 euros.

Resistance Mechanisms

1. Increased Expression of the ABCB1 and ABCC11 Genes: ATP-binding cassette transporters (ABCB1 and ABCC11) confer treatment resistance by pumping the drug out of cells.
2. Activation of the NF-κB Signaling Pathway: NF-κB is a signaling pathway that supports cell survival. Overactivation of this pathway may cause cancer cells to develop resistance to the drug.
3. Activation of the PI3K Signaling Pathway: The PI3K signaling pathway promotes cell growth and survival. Overactivation of this pathway may make cancer cells resistant to eribulin.

Absorption

Eribulin is administered only intravenously (IV), so it is not absorbed through the gastrointestinal tract.

Distribution

Eribulin is distributed rapidly and extensively. Its mean volume of distribution ranges from 43–114 L/m². Eribulin binds variably to plasma proteins, with binding ranging between 49% and 65%.

Metabolism

Eribulin has no major metabolite. Excretion occurs mainly through the hepatobiliary route, with 82% of the parent drug excreted in feces. A small proportion is excreted in urine (9%). The drug's mean half-life is approximately 40 hours.

Drug Interactions

• Caution is required when it is used with drugs that prolong the QTc interval.
• Drugs that interact with eribulin include “arsenik triosit”, astemizole, bepridil, certain phenothiazines (chlorpromazine, mesoridazine, thioridazine), chloroquine, clarithromycin, class IA antiarrhythmics (disopyramide, procainamide, quinidine), class III antiarrhythmics (amiodarone, bretylium, dofetilide, ibutilide, sotalol), “deksametorfan”, erythromycin, grepafloxacin, halofantrine, haloperidol, methadone, pentamidine, posaconazole, saquinavir, sparfloxacin, terfenadine, and troleandomycin.

Dosage Range

The recommended dose of eribulin is as follows:

In 21-day cycles, on days 1 and 8, by intravenous infusion, 1.4 mg/m² is administered.

Precautions

• Sedative Effect and Cardiac Risks: Since eribulin may prolong the QTc interval, it should be used cautiously in patients with a prolonged QTc interval or a history of cardiac disease. Caution is also required when it is combined with other drugs that prolong the QT interval.
• Kidney Function: A lower starting dose is recommended for patients with moderate renal impairment (CrCl 30-50 mL/min). Safety has not been established in patients with severe renal impairment (CrCl <30 mL/min).
• Liver Function: A lower starting dose (1.1 mg/m²) is recommended in patients with mild hepatic impairment (Child-Pugh Class A). In patients with moderate hepatic impairment (Child-Pugh Class B), a dose of 0.7 mg/m² is recommended. There are no safety data for patients with severe hepatic impairment (Child-Pugh Class C).
• Pregnancy and Breastfeeding: Eribulin is in pregnancy category D. Its use during pregnancy is not recommended, and it should not be used while breastfeeding.
• Myelosuppression: Eribulin may suppress bone marrow function. Blood counts should therefore be monitored regularly during treatment.
• Drug Interactions: It should not be used with drugs that prolong the QTc interval. In addition, because eribulin targets microtubules, caution is required when using it with other microtubule modulators.

Adverse Effects

Adverse effects in order of frequency:

• Myelosuppression: Eribulin may cause myelosuppression with dose-limiting neutropenia. Thrombocytopenia and anemia are observed less frequently.
• Fatigue, Asthenia, and Anorexia: Fatigue, weakness, and loss of appetite are common adverse effects during eribulin treatment.
• Gastrointestinal Adverse Effects: Gastrointestinal problems such as nausea/vomiting, mucositis, diarrhea, dyspepsia, and dry mouth may occur.
• Peripheral Neuropathy: Eribulin may cause peripheral neuropathy. This may cause patients to experience neurological symptoms such as pain or numbness.
• QTc Prolongation: Prolongation of the QTc interval may occur rarely. Caution is required during treatment because this may lead to heart rhythm problems.