Side Effects of Halaven (eribulin mesylate)

Halaven (eribulin mesylate) is a chemotherapeutic medicine approved to treat metastatic breast cancer, an advanced form of breast cancer that has spread to other parts of the body.

Microtubules are dynamic intracellular structures that are responsible for various kinds of movements including cell division, organization of intracellular structure, and intracellular transport. Halaven inhibits the growth phase of microtubules, consequently interfering with cell growth and function and eventually causing cancer cell death.

Halaven was developed from a chemical first isolated from the rare marine sponge, Halichondria okadai. Halaven can help some patients with metastatic breast cancer live longer. In one trial, women treated with Halaven lived about 2.5 months longer than women who received other treatments. 

Common side effects of Halaven include

• low white blood cells,
• low red blood cells,
• weakness,
• tiredness,
• hair loss,
• constipation,
• nausea, and
• numbness, tingling, or burning in the hands and feet.

Serious side effects of Halaven include

• decreased white blood cell counts (neutropenia) which may increase the risk for serious infections that can lead to hospitalization or death, changes in the heartbeat rhythm that can potentially cause death, and damage the kidney or liver. 

Drug interactions of Halaven include other drugs that cause abnormal heart beats because it can increase the risk of developing abnormal heart beats.

Halaven has not been adequately evaluated in pregnant women. However, based on the mechanism in which Halaven works in the body, it is expected to harm a fetus and therefore, should not be used during pregnancy.

It is unknown if Halaven is excreted in breast milk. As many drugs enter breast milk and can potentially cause harm to the nursing infant, Halaven is not recommended in breastfeeding mothers.

The most common side effects of eribulin are:

• low white blood cells,
• low red blood cells,
• weakness,
• tiredness,
• hair loss,
• constipation,
• nausea, and
• numbness, tingling, or burning in the hands and feet (peripheral neuropathy).

The most common serious side effect is decreased white blood cell counts or neutropenia. White blood cells are necessary to fight infections; therefore, significantly low levels of white blood cells may increase the risk for serious infections that can lead to hospitalization or death.

Peripheral neuropathy (damage to the nerves of the extremities) is the most common side effect that causes patients to stop taking eribulin. Severe peripheral neuropathy occurred in 8% of patients treated with eribulin. Furthermore, 5% of patients experienced neuropathy lasting more than 1 year, while 22% of patients developed new or worsening neuropathy that did not get better after an average of 269 days.

Eribulin also can cause abnormalities in the electrocardiogram such as QT prolongation and changes in the heartbeat rhythm that can potentially cause death.

Eribulin can damage the kidney or liver. Risk for injury is higher in patients who have pre-existing kidney or liver disease. To avoid serious injury, such patients should be treated with a lower dose of eribulin.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

The following adverse reactions are discussed in detail in other sections of the labeling:

• Neutropenia
• Peripheral neuropathy
• QT prolongation

In clinical trials, Halaven has been administered to 1963 patients including 467 patients exposed to Halaven for 6 months or longer. The majority of the 1963 patients were women (92%) with a median age of 55 years (range: 17 to 85 years).

The racial and ethnic distribution was

• White (72%),
•  Black (4%),
• Asian (9%), and
• other (3%).

Metastatic Breast Cancer

The most common adverse reactions ( ≥ 25%) reported in patients receiving Halaven were

• neutropenia,
•  anemia,
• asthenia/fatigue,
• alopecia,
• peripheral neuropathy,
• nausea, and
• constipation.

The most common serious adverse reactions reported in patients receiving Halaven were

• febrile neutropenia (4%) and
• neutropenia (2%).

The most common adverse reaction resulting in discontinuation of Halaven was peripheral neuropathy (5%).

The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1.

• In Study 1, patients were randomized (2:1) to receive either Halaven (1.4 mg/m² on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group).
• A total of 503 patients received Halaven and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%).
• The median duration of exposure was 118 days for patients receiving Halaven and 63 days for patients receiving control therapy.
• Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.

Table 2: Adverse Reactions^a with a Per-Patient Incidence of at Least 10% in Study 1

Cytopenias

• Grade 3 neutropenia occurred in 28% (143/503) of patients who received Halaven in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia.
• Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia.
• Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in < 1% of patients.

The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia ( < 500/mm³>) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte-macrophage colony-stimulating factor) was used in 19% of patients who received Halaven.

Peripheral Neuropathy

• In Study 1, 17 % of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline.
• Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received Halaven.
• Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.

Liver Function Test Abnormalities

• Among patients with Grade 0 or 1 ALT levels at baseline, 18% of Halaven-treated patients experienced Grade 2 or greater ALT elevation.
• One Halaven-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to Halaven.

Less Common Adverse Reactions

The following additional adverse reactions were reported in ≥ 5% to < 10% of the Halaven-treated group:

• Eye Disorders: increased lacrimation
• Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth
• General Disorders and Administration Site Conditions: peripheral edema
• Infections and Infestations: upper respiratory tract infection
• Metabolism and Nutrition Disorders: hypokalemia
• Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness
• Nervous System Disorders: dysgeusia, dizziness
• Psychiatric Disorders: insomnia, depression
• Skin and Subcutaneous Tissue Disorders: rash

Liposarcoma

• The safety of Halaven was evaluated in Study 2, an open-label, randomized, multicenter, active-controlled trial, in which patients were randomized (1:1) to receive either Halaven 1.4 mg/m² on Days 1 and 8 of a 21-day cycle or dacarbazine at doses of 850 mg/m² (20%), 1000 mg/m² (64%), or 1200 mg/m² (16%) every 3 weeks.
• A total of 223 patients received Halaven and 221 patients received dacarbazine.
• Patients were required to have received at least two prior systemic chemotherapy regimens.
• The trial excluded patients with pre-existing ≥ Grade 3 peripheral neuropathy, known central nervous system metastasis, elevated serum bilirubin or significant chronic liver disease, history of myocardial infarction within 6 months, history of New York Heart Association Class II or IV heart failure, or cardiac arrhythmia requiring treatment.
• The median age of the safety population in Study 2 was
  • 56 years (range: 24 to 83 years);
  • 67% female;
  • 73% White,
  • 3% Black or African American,
  • 8% Asian/Pacific Islander, and
  • 15% unknown;
  • 99% received prior anthracycline-containing regimen; and
  • 99% received = 2 prior regimens.
  • The median duration of exposure was 2.3 months (range: 21 days to 26 months) for patients receiving Halaven.

The most common adverse reactions ( ≥ 25%) reported in patients receiving Halaven were

• fatigue,
• nausea,
• alopecia,
• constipation,
• peripheral neuropathy,
• abdominal pain, and
• pyrexia.

The most common ( ≥ 5%) Grade 3-4 laboratory abnormalities reported in patients receiving Halaven were

• neutropenia,
• hypokalemia, and
• hypocalcemia.

The most common serious adverse reactions reported in patients receiving Halaven were

• neutropenia (4.9 %) and
• pyrexia (4.5%).

Permanent discontinuation of Halaven for adverse reactions occurred in 8% of patients. The most common adverse reactions resulting in discontinuation of Halaven were

• fatigue and
• thrombocytopenia (0.9% each).

Twenty-six percent of patients required at least one dose reduction. The most frequent adverse reactions that led to dose reduction were

• neutropenia (18%) and
• peripheral neuropathy (4.0%).

Table 3 summarizes the incidence of adverse reactions occurring in at least 10% of patients in the Halaven-treated arm in Study 2.

Table 3: Adverse Reactions^a Occurring in ≥ 10% (all Grades) of Patients Treated on the Halaven arm and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥ 5% for All Grades or ≥ 2% for Grades 3 and 4) (Study 2)^b

Other clinically important adverse reactions occurring in ≥ 10% of the Halaven-treated patients were:

• Gastrointestinal Disorders: nausea (41%); vomiting (19%), diarrhea (17%)
• General Disorders: asthenia/fatigue (62%); peripheral edema (12%)
• Metabolism and Nutrition Disorders: decreased appetite (19%)
• Musculoskeletal and Connective Tissue Disorders: arthralgia/myalgia (16%); back pain (16%)
• Respiratory Disorders: cough (18%)

Less Common Adverse Reactions

The following additional clinically important adverse reactions were reported in ≥ 5% to < 10% of the Halaven-treated group:

• Blood and Lymphatic System Disorders: thrombocytopenia
• Eye Disorders: increased lacrimation
• Gastrointestinal Disorders: dyspepsia
• Metabolism and Nutrition Disorders: hyperglycemia
• Musculoskeletal and Connective Tissue Disorders: muscle spasms, musculoskeletal pain
• Nervous System Disorders: dizziness, dysgeusia
• Psychiatric Disorders: insomnia, anxiety
• Respiratory, Thoracic, and Mediastinal Disorders: oropharyngeal pain
• Vascular Disorders: hypotension

Table 4: Laboratory Abnormalities Occurring in ≥ 10% (all Grades) of Patients Treated on the Halaven arm and at a Higher Incidence than in the Dacarbazine Arm (Between Arm Difference of ≥ 5% forAll Grades or ≥ 2% for Grades 3 and 4)^a (Study 2)†

Postmarketing Experience

The following adverse drug reactions have been identified during post-approval of Halaven. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Blood and Lymphatic System Disorders: lymphopenia
• Gastrointestinal Disorders: pancreatitis
• Hepatobiliary Disorders: hepatotoxicity
• Immune System Disorders: drug hypersensitivity
• Infections and Infestations: pneumonia, sepsis/neutropenic sepsis
• Metabolism and Nutrition Disorders: hypomagnesemia, dehydration
• Respiratory, thoracic and mediastinal disorders: interstitial lung disease
• Skin and Subcutaneous Tissue Disorders: pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis

Effects Of Other Drugs On Halaven

• No drug-drug interactions are expected with CYP3A4 inhibitors, CYP3A4 inducers or P-glycoprotein (P-gp) inhibitors.
• Clinically meaningful differences in exposure (AUC) were not observed in patients with advanced solid tumors when Halaven was administered with or without ketoconazole (a strong inhibitor of CYP3A4 and a P-gp inhibitor) and when Halaven was administered with or without rifampin (a CYP3A4 inducer).

Effect Of Halaven On Other Drugs

• Eribulin does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 enzymes or induce CYP1A2, CYP2C9, CYP2C19 or CYP3A4 enzymes at relevant clinical concentrations.
• Eribulin is not expected to alter the plasma concentrations of drugs that are substrates of these enzymes.