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Eribulin, a Microtubule Inhibitor for Metastatic Breast Cancer

Eribulin, a Microtubule Inhibitor for Metastatic Breast Cancer

Approved Drug: Eribulin mesylate (Halaven)

Indications
Treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic breast cancer.

Mechanism of Action
Eribulin mesylate is a microtubule inhibitor. It prevents the microtubules from growing but does not affect the shortening of the microtubules in mitosis, making the tubulin nonfunctional. This causes the cell to stop in the G2/M phase of the cell cycle, which disrupts the mitotic spindles and causes cell death as a result of prolonged mitotic blockage.

Metabolism
After IV administration, the human plasma protein binding of eribulin at concentrations of 100 ng/mL to 1,000 ng/mL ranges from 49% to 65%, and drug is eliminated (mean elimination half-life) in 40 hours. The drug is primarily metabolized in the liver by the cytochrome P450 microenzyme system CYP3A4. It is unlikely to increase plasma levels of CYP3A4 substrates, or induce the microenzymes. Eribulin mesylate is a substrate and weak inhibitor of the P-glycoprotein (P-gp), the drug efflux transporter. There are no major clinically significant metabolites, and there is no accumulation of the drug with weekly dosing. When drug was administered to patients with mild or moderate hepatic impairment, eribulin mesylate exposure increased 1.8-fold and 2.5-fold, respectively. When administered to patients with moderate renal impairment, the dose-normalized systemic exposure increased 2-fold, compared with patients with normal renal function. The drug is eliminated primarily unchanged in the feces (82%) and to a lesser degree in the urine (9%).

Drug Administration
1.4 mg/m2 IV over 2 to 5 minutes on days 1 and 8 of a 21-day cycle. Administer as IVP, or dilute in 100 mL 0.9% Sodium Chloride Injection, USP.

• Drug is available as 1 mg/2 mL (0.5 mg/mL). Store undiluted in the syringe, or diluted drug, for up to 4 hours at room temperature, or for up to 24 hours refrigerated (40°F/4°C).

• Do not administer in cases of ANC < 1,000/mm3, platelets < 75,000/mm3, or grade 3 or 4 nonhematologic toxicity.

• Do not mix with other drugs, or administer with dextrose-containing solutions.

• Day 8 dose may be delayed a maximum of 1 week: if toxicities do not resolve or improve to ≤ grade 2 severity by day 15, omit the dose; if toxicities resolve or improve to ≤ grade 2 severity by day 15, administer eribulin mesylate at a reduced dose (see below), and initiate the next cycle no sooner than 2 weeks later.

• If a dose has been delayed for toxicity, and toxicities have recovered to ≤ grade 2 severity, resume at a reduced dose (see below); do not re-escalate eribulin mesylate after it has been dose-reduced.

• Reduce dose to 1.1 mg/m2 for any of the following:
– ANC < 500/mm3 for > 7 days
– ANC < 1,000/mm3 with fever or infection
– Platelets < 25,000/mm3
– Platelets < 50,000/mm3, requiring transfusion
– Nonhematologic grade 3 or 4 toxicities
– Omission or delay of day 8 eribulin mesylate in previous cycle for toxicity

• Dose-reduce to 0.7 mg/m2 for the occurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2.

• While receiving a dose of 0.7 mg/m2, if any event requiring permanent dose reduction occurs, discontinue drug.

• Dose-reduce in patients with hepatic impairment or moderate renal impairment.

• Starting dose for patients with mild (Child-Pugh A) hepatic impairment: 1.1 mg/m2.

• Starting dose for patients with moderate (Child-Pugh B) hepatic impairment: 0.7 mg/m2.

• Starting dose for patients with moderate renal impairment (CrCl 30-50 mL/min): 1.1 mg/m2.

Patient Education
Educate patients about eribulin as follows:

The most common side effects of drug are low neutrophil count with risk of infection, anemia (low red blood cell count), feeling very tired (asthenia/fatigue), hair loss (alopecia), pins and needles in the fingers and toes (peripheral neuropathy), feeling sick to your stomach (nausea), and constipation.

Drug can cause a decrease in your white blood cell count (neutrophils that fight against infection) and red blood cells, so your blood counts will be monitored closely, and your drug dose may need to be changed or delayed. This can increase your risk of getting an infection.

• Report any signs and/or symptoms of infection (eg, fever of 100.4°F or higher, chills, cough, shortness of breath, burning on urination, bleeding) to your doctor right away.

• Avoid contact with people with colds, large crowds, and very young children, as this may expose you to infection.

• Drug can cause numbness and tingling or burning in your fingers/hands and toes/feet, called peripheral neuropathy. Tell your doctor or nurse if these occur, or if you have any difficulty with activities of daily living, such as buttoning your shirt or walking.

• Fatigue will occur; it is important to try to save energy and rest, so ask your nurse to tell you ways to minimize fatigue, such as alternating rest and activity periods; do not operate any dangerous tools or machinery if fatigued.

• Drug may prolong a portion of the ECG that reflects the electrical activity of the heart. The risk increases if you have low levels of certain electrolytes (such as magnesium) in your blood or if you are taking certain drugs. You will have ECGs done before you start the treatment and periodically during therapy. You will have blood tests which check your electrolytes, and if they are low, you will have the electrolytes replaced. Tell your doctor all the drugs you take, and also if you have a history of congestive heart failure (CHF), a slow heart beat, or were born with a syndrome called congenital long QT syndrome.

• Women of child-bearing potential should use effective birth-control measures to prevent pregnancy, as the drug may harm the fetus. Mothers should not nurse while receiving the drug.

Drug Interactions
No drug-drug interactions with CYP3A4 inhibitors or P-gp inhibitors.

• No drug-drug inhibition or induction of P450 microenzymes, so drug should not alter plasma concentrations of drugs that are substrates of these enzymes.

Special Considerations
Neutropenia occurred in 82% of patients, with 28% grade 3 and 29% grade 4. Febrile neutropenia occurred in 5% of patients. In clinical studies, 0.4% of patients died from febrile neutropenia. Dose reductions were required in 12% of patients. Mean time to nadir is 13 days, mean time to recovery from severe neutropenia (< 500/mm3) was 8 days. Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) was used in 19% of patients.

• Grade 3/4 thrombocytopenia occurred in 1% of patients.

• Monitor for signs of both motor and sensory peripheral neuropathy (PN) prior to each dose. PN occurs in 35% of patients. Grade 3 PN occurred in 8% of patients, grade 4 in 0.4%; however, PN was the most common toxicity causing discontinuation. PN lasted > 1 year in 5% of patients, while 22% developed a new or worsening PN that persisted for at least a median follow-up of 269 days. Hold drug if patient has grade 3 or 4 PN until PN resolves to grade 2 or less, then adjust dose.

• In an uncontrolled open-label ECG study in 26 patients, QT-prolongation was identified on day 8; this was independent of the eribulin mesylate concentration. Monitor ECG in patients with CHF, bradyarrhythmias, those who are taking drugs known to prolong the QT interval (eg, Class Ia and III antiarrhythmics), and those with electrolyte abnormalities. Assess for and correct hypokalemia or hypomagnesemia prior to beginning eribulin mesylate, and monitor these electrolytes during therapy.

• Drug may cause embryo-fetal toxicity and teratogenicity. If the drug is used in a pregnant woman, or if the patient becomes pregnant while receiving the drug, apprise her of the potential risks to the fetus. It is unknown if the drug is excreted in breast milk, so women who are breastfeeding should either stop nursing or discontinue the drug.

• Patients may develop liver function test abnormalities. Of those with grade 0–1 ALT at baseline, 18% of patients developed grade 2 or higher ALT elevations, which resolved and did not recur with re-exposure to the drug.

• In the study population, only 15% were aged 65 years or older, and 2% were 75 years or older. There were no overall differences in safety between this population and younger patients.

Contraindications/Precautions
None

• Avoid using drug in patients with congenital long QT syndromes; drug safety has not been studied in patients with severe hepatic impairment (Child-Pugh C) or with severe renal impairment (CrCl < 30 mL/min), and there is no known antidote.

Adverse Reactions to Eribulin by System (boldface type indicates more common events, > 20%)

CNS: Peripheral neuropathy, headache, increased lacrimation, dysgeusia, dizziness, insomnia, depression
CV:
Prolongation of QT interval (≥ 500 msec) at day 8
GI: Constipation, nausea, decreased weight, anorexia, diarrhea, vomiting, dyspepsia, abdominal pain, stomatitis, dry mouth, increased ALT
GU: Urinary tract infection
Hematologic: Neutropenia, anemia, thrombocytopenia, febrile neutropenia
Metabolic: Hypomagnesemia
Musculoskeletal: Arthalgia/myalgia, muscle spasms, muscular weakness, back pain, bone pain, pain in extremity
Respiratory: Cough, dyspnea, upper respiratory tract infection
Reproductive: Fetal injury
Skin: Alopecia, peripheral edema, mucosal inflammation
Other: Fever, fatigue, asthenia

 
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