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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 [see WARNINGS AND PRECAUTIONS].
- Peripheral neuropathy [see WARNINGS AND PRECAUTIONS].
- QT interval prolongation [see WARNINGS AND PRECAUTIONS].
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%).
In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).
The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1 [see Clinical Studies]. 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 with a Per-Patient
Incidence of at Least 10% in Study 1
|MedDRA ver 10.0||HALAVEN
|All Grades||≥ Grade 3||All Grades||≥ Grade 3|
|Blood and Lymphatic System Disordersa|
|Nervous system disorders|
|Headache||19%||< 1%||12%||< 1%|
|General disorders and administrative site conditions|
|Pyrexia||21%||< 1%||13%||< 1%|
|Musculoskeletal and connective tissue disorders|
|Pain in extremity||11%||1%||10%||1%|
|Weight decreased||21%||1%||14%||< 1%|
|Metabolism and nutrition disorders|
|Respiratory, thoracic, and mediastinal disorders|
|Skin and subcutaneous tissue disorders|
|Infections and Infestations|
|Urinary Tract Infection||10%||1%||5%||0|
|a based upon laboratory data.
b includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia.
c not applicable; (grading system does not specify > Grade 2 for alopecia).
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 colonystimulating 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
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
Read the Halaven (eribulin mesylate) Side Effects Center for a complete guide to possible side effects
Effects Of Other Drugs On HALAVEN
No drug-drug interactions are expected with CYP3A4 inhibitors, CYP3A4 inducers or P-glycoprotein (Pgp) 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) [see CLINICAL PHARMACOLOGY].
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 [see CLINICAL PHARMACOLOGY].
Read the Halaven Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 1/15/2016
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