Halaven Drug Information

Me tastatic Breast Cancer HALAVEN is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Liposarcoma HALAVEN is indicated for the treatment of patients with unresectable or metastatic liposarcoma who have received a prior anthracycline-containing regimen.

Instructions for Preparation and Administration

Aseptically withdraw the required amount of HALAVEN from the single-dose vial and administer undiluted or diluted in 100 mL of 0.9% Sodium Chloride Injection, USP. Do not dilute in or administer through an intravenous line containing solutions with dextrose. Do not administer in the same intravenous line concurrent with the other medicinal products.

Store undiluted HALAVEN in the syringe for up to 4 hours at room temperature or for up to 24 hours under refrigeration at 4°C (40°F). Store diluted solutions of HALAVEN for up to 4 hours at room temperature or up to 24 hours under refrigeration at 4°C (40°F). Discard unused portions of the vial.

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. 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.

A total of 503 patients received Halaven and 247 patients in the control group received therapy consisting of chemotherapy 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.

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/mm 3 ) 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. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received Halaven.

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/m 2 on Days 1 and 8 of a 21-day cycle or dacarbazine at doses of 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 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 Other clinically important adverse reactions occurring in ≥10% of the Halaven-treated patients were: Gastrointestinal Disorders: nausea (4 ) 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 6. 2 Post ma rketing 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 s 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.

Pregnancy Risk Summary Based on findings from an animal reproduction study and its mechanism of action, HALAVEN can cause fetal harm when administered to a pregnant woman. There are no available data on the use of HALAVEN during pregnancy. In an animal reproduction study, eribulin mesylate caused embryo-fetal toxicity when administered to pregnant rats during organogenesis at doses below the recommended human dose.

Advise pregnant women of the potential risk to a fetus. The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is respectively.

Data Animal Data In an embryo-fetal developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately times the recommended human dose, based on body surface area. Increased abortion and severe fetal external or soft tissue malformations, including the absence of a lower jaw and tongue, or stomach and spleen, were observed at doses 0.64 times the recommended human dose of 1.4 mg/m 2 based on body surface area. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at doses at or above a maternally toxic dose of approximately 0.43 times the recommended human dose.

Pediatric Use The safety and effectiveness of HALAVEN in pediatric patients have not been established. The safety and effectiveness of HALAVEN alone or in combination with irinotecan in pediatric patients were assessed but not established in three open-label studies (NCT02171260, NCT03441360, and NCT03245450) in 77 pediatric patients aged 2 to <17 years with relapsed or refractory solid tumors and lymphomas, excluding central nervous system tumors. No new safety signals were observed in these studies.

The pharmacokinetics (PK) of eribulin were within range of values of adult patients with metastatic liposarcoma or other tumors given the same dose per body surface area.

Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day. There is no known antidote for HALAVEN overdose.