Halaven Injection

HALAVEN contains eribulin mesylate, a microtubule dynamics inhibitor. Eribulin mesylate is a synthetic analogue of halichondrin B, a product isolated from the marine sponge Halichondria okadai. The chemical name for eribulin mesylate is 11,15:18,21:24,28Triepoxy-7,9-ethano-12,15-methano-9H,15H-furo[3,2-i]furo[2',3':5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one, 2-[(2S)-3amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, methanesulfonate (salt). It has a molecular weight of 826.0 (729.9 for free base). The empirical formula is C40H59NO11 •CH4O3S. Eribulin mesylate has the following structural formula:

HALAVEN is a clear, colorless, sterile solution for intravenous administration. Each vial contains 1 mg of eribulin mesylate as a 0.5 mg/mL solution in ethanol: water (5:95).

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 prolongation [see WARNINGS AND PRECAUTIONS]

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%).

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 [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 Reactionsa 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

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 [see Clinical Studies].

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 Reactionsa 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

Included as part of the PRECAUTIONS section.

HALAVEN®
(HAL-ih-ven)
(Eribulin Mesylate) Injection, For Intravenous Use

What is the most important information I should know about HALAVEN?

HALAVEN can cause serious side effects, including:

• Low white blood cell count (neutropenia). This can lead to serious infections that could lead to death. Your healthcare provider will check your blood cell counts before you receive each dose of HALAVEN and during treatment. Call your healthcare provider right away if you develop any of these symptoms of infection:
  • fever (temperature above 100.5°F)
  • chills
  • cough
  • burning or pain when you urinate
• Numbness, tingling, or pain in your hands or feet (peripheral neuropathy). Peripheral neuropathy is common with HALAVEN and sometimes can be severe. Tell your healthcare provider if you have new or worsening symptoms of peripheral neuropathy.
• Your healthcare provider may delay, decrease your dose, or stop treatment with HALAVEN if you have side effects.

See “What are possible side effects of HALAVEN?” for more information about side effects.

What is HALAVEN?

HALAVEN is a prescription medicine used to treat people with:

• Breast cancer
  • that has spread to other parts of the body, and
  • who have already received certain types of anticancer medicines after the cancer has spread
• Liposarcoma
  • that cannot be treated with surgery or has spread to other parts of the body, and
  • who have received treatment with a certain type of anticancer medicine

It is not known if HALAVEN is safe and effective in children under 18 years of age.

Before you receive HALAVEN, tell your healthcare provider about all of your medical conditions, including if you:

• have liver or kidney problems
• have heart problems, including a problem called congenital long QT syndrome
• have low potassium or low magnesium in your blood
• are pregnant or plan to become pregnant. HALAVEN can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with HALAVEN.
  • Females who are able to become pregnant should use an effective birth control during treatment with HALAVEN and for at least 2 weeks after the final dose of HALAVEN.
  • Males should use an effective form of birth control when having sex with female partners who are able to become pregnant during treatment with HALAVEN and for 3 ½ months (14 weeks) after the final dose of HALAVEN.
• are breastfeeding or plan to breastfeed. It is not known if HALAVEN passes into your breast milk. Do not breastfeed during treatment with HALAVEN and for 2 weeks after the final dose of HALAVEN.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How will I receive HALAVEN?

• HALAVEN is given by intravenous (IV) injection in your vein.
• HALAVEN is given in “cycles” of treatment, with each cycle lasting 21 days.
• HALAVEN is usually given on day 1 and day 8 of a treatment cycle.

What are the possible side effects of HALAVEN?

HALAVEN may cause serious side effects, including:

• See “What is the most important information I should know about HALAVEN?”
• HALAVEN can cause changes in your heartbeat (called QT prolongation). This can cause irregular heartbeats. Your healthcare provider may do heart monitoring (electrocardiogram or ECG) or blood tests during your treatment with HALAVEN to check for heart problems.

The most common side effects of HALAVEN in people with breast cancer include:

• low white blood cell count (neutropenia)
• low red blood cell count (anemia)
• weakness or tiredness
• hair loss (alopecia)
• nausea
• constipation

The most common side effects of HALAVEN in people with liposarcoma include:

• tiredness
• nausea
• hair loss (alopecia)
• constipation
• stomach pain
• fever

Your healthcare provider will do blood tests before and during treatment while you are taking HALAVEN. The most common changes to blood tests in people with liposarcoma include:

• low white blood cell count (neutropenia)
• decreased blood levels of potassium or calcium

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of HALAVEN. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about HALAVEN

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about HALAVEN that is written for health professionals.

What are the ingredients in HALAVEN?

Active Ingredient: eribulin mesylate

Inactive Ingredients: ethanol, water