Halaven (Page 2 of 7)

5.3 Embryo – Fetal Toxicity

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 adequate and well-controlled studies of HALAVEN in pregnant women. In animal reproduction studies, 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. Advise females of reproductive potential to use effective contraception during treatment with HALAVEN and for at least 2 weeks following the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with HALAVEN and for 3.5 months following the final dose [see Use in Specific Populations (8.1)].

5.4 QT Prolongation

In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome.

6 ADVERSE REACTIONS

6.1 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 (5.1)]
  
• Peripheral neuropathy [see Warnings and Precautions (5.2)]
• QT prolongation [see Warnings and Precautions (5.4)]

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 [ see Clinical Studies (14.1)]. 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

Adverse Reactions	HALAVEN n=503		Control Group n=247
	All Grades	≥ Grade 3	All Grades	≥ Grade 3
Blood and l ymphatic s ystem d isorders b
Neutropenia	82%	57%	53%	23%
Anemia	58%	2%	55%	4%
Nervous system disorders
Peripheral neuropathyc	35%	8%	16%	2%
Headache	19%	<1%	12%	<1%
General disorders
Asthenia/Fatigue	54%	10%	40%	11%
Pyrexia	21%	<1%	13%	<1%
Mucosal inflammation	9%	1%	10%	2%
Gastrointestinal disorders
Nausea	35%	1%	28%	3%
Constipation	25%	1%	21%	1%
Vomiting	18%	1%	18%	1%
Diarrhea	18%	0	18%	0
Musculoskeletal and connective tissue disorders
Arthralgia/Myalgia	22%	<1%	12%	1%
Back pain	16%	1%	7%	2%
Bone pain	12%	2%	9%	2%
Pain in extremity	11%	1%	10%	1%
Metabolism and nutrition disorders
Decreased weight	21%	1%	14%	<1%
Anorexia	20%	1%	13%	1%
Respiratory, thoracic, and mediastinal disorders
Dyspnea	16%	4%	13%	4%
Cough	14%	0	9%	0
Skin and subcutaneous tissue disorders
Alopecia	45%	NAd	10%	NAd
Infections
Urinary Tract Infection	10%	1%	5%	0
a adverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.0. b based upon laboratory data.c includes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia.d 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 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 [ see Clinical Studies (14.2)].

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

Adverse Reaction	HALAVEN n =22 3		Dacarbazine n =22 1
	All Grades	Grades 3-4	All Grades	Grades 3-4
Nervous s ystem d isorders
Peripheral Neuropathyc	29%	3.1%	8%	0.5%
Headache	18%	0%	10%	0%
General d isorders
Pyrexia	28%	0.9%	14%	0.5%
G astrointestinal d isorders
Constipation	32%	0.9%	26%	0.5%
Abdominal paind	29%	1.8%	23%	4.1%
Stomatitis	14%	0.9%	5%	0.5%
Skin and s ubcutaneous t issue d isorders
Alopecia	35%	NAe	2.7%	NAe
Infections
Urinary tract infection	11%	2.2%	5%	0.5%
a Adverse reactions were graded per National Cancer Institute Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03).b Safety data from one study site enrolling six patients were excluded.c Includes peripheral neuropathy, peripheral sensorimotor neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia.d Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort.e Not applicable; (grading system does not specify > Grade 2 for alopecia).

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% for All Grades or ≥2% for Grades 3 and 4)^a (Study 2)^†

Laboratory Abnormality	H alaven		Dacarbazine
	All Grades	Grades 3 — 4	All Grades	Grades 3 – 4
Hematology
Anemia	70%	4.1%	52%	6%
Neutropenia	63%	32%	30%	8.9%
Chemistry
Increased alanine aminotransferase (ALT)	43%	2.3%	28%	2.3%
Increased aspartate aminotransferase (AST)	36%	0.9%	16%	0.5%
Hypokalemia	30%	5.4%	14%	2.8%
Hypocalcemia	28%	5%	18%	1.4%
Hypophosphatemia	20%	3.2%	11%	1.4%
a Each test incidence is based on the number of patients who had both baseline and at least one on-study measurement and at least 1 grade increase from baseline.Halaven group (range 221-222) and dacarbazine group (range 214-215)† Laboratory results were graded per NCI CTCAE v4.03.