Halaven

Eribulin is a cancer medicine that interferes with the growth and spread of cancer cells in the body.

Eribulin is used to treat breast cancer that has spread to other parts of the body.

Eribulin is also used to treat liposarcoma, a rare type of cancer that develops in fatty tissue anywhere in the body. Eribulin is used for liposarcoma that cannot be treated with surgery, or has spread throughout the body.

Eribulin is usually given after at least 2 other combinations of chemotherapy medications have been tried without successful treatment of symptoms.

Eribulin may also be used for purposes not listed in this medication guide.

Eribulin can lower blood cells that help your body fight infections and help your blood to clot. You may get an infection or bleed more easily. Call your doctor if you have unusual bruising or bleeding, or signs of infection (fever, chills, cough, pain or burning when you urinate).

You should not use eribulin if you are allergic to it.

To make sure eribulin is safe for you, tell your doctor if you have:

• liver disease;
• kidney disease;
• heart disease;
• peripheral vascular disease such as Raynaud's syndrome;
• personal or family history of long QT syndrome; or
• an electrolyte imbalance (such as low levels of potassium or magnesium in your blood).

Do not use eribulin if you are pregnant. It could harm the unborn baby. Tell your doctor if you become pregnant during treatment. Use effective birth control to prevent pregnancy while using eribulin, and for at least 2 weeks after your last dose.

If a man fathers a baby while using eribulin, the baby may have birth defects. Use condoms to prevent pregnancy during your treatment, and for at least 14 weeks (3.5 months) after your last dose.

It is not known whether eribulin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using eribulin.

Before you receive Halaven, tell your healthcare provider if you:

• have liver or kidney problems
• have heart problems, including a problem called "congenital long QT syndrome"
• are pregnant or plan to become pregnant
• are breastfeeding or planning to breastfeed

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

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Halaven falls into category D. There are no well done studies in pregnant women. In animal studies, pregnant animals were given this medication and had some babies born with problems. This medication is expected to cause fetal harm when administered to a pregnant woman. However, in some serious situations, the benefit of using this medication may be greater than the risk of harm to the baby.

Tell your healthcare provider if you are breastfeeding or planning to breastfeed. It is not known if Halaven passes into your breast milk. You and your healthcare provider should decide if you will take Halaven or breastfeed. You should not do both.

You should not use eribulin if you are allergic to it.

To make sure eribulin is safe for you, tell your doctor if you have:

• liver disease;

• kidney disease;

• heart disease;

• peripheral vascular disease such as Raynaud's syndrome;

• personal or family history of long QT syndrome; or

• an electrolyte imbalance (such as low levels of potassium or magnesium in your blood).

Do not use eribulin if you are pregnant. It could harm the unborn baby. Tell your doctor if you become pregnant during treatment. Use effective birth control to prevent pregnancy while using eribulin, and for at least 2 weeks after your last dose.

If a man fathers a baby while using eribulin, the baby may have birth defects. Use condoms to prevent pregnancy during your treatment, and for at least 14 weeks (3.5 months) after your last dose.

It is not known whether eribulin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using eribulin.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Absorption

Plasma Concentrations

Following IV administration, plasma concentrations decline in a triphasic manner with an initial rapid distribution phase followed by a slower elimination phase.4 7 10 13 26 36

Special Populations

In patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, exposure increased approximately 1.8- or 2.5-fold, respectively.1 8 (See Hepatic Impairment under Cautions.)

Formal pharmacokinetic studies in patients with renal impairment not conducted.1 Exposure increased twofold in patients with moderate renal impairment (Clcr 30–50 mL/minute).1 (See Renal Impairment under Cautions.)

Distribution

Extent

Not known whether distributed into human milk.1

Plasma Protein Binding

49–65%.1

Elimination

Metabolism

Primarily metabolized by cytochrome CYP3A4; no major human metabolites detected.1 10 13

Elimination Route

Eliminated mainly as unchanged drug in feces (82%) and in urine (9%).1

Half-life

Terminal elimination half-life approximately 40 hours.1 19 26

No accumulation observed with weekly administration.1

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of eribulin injection in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of eribulin injection in the elderly.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amifampridine
• Amisulpride
• Bepridil
• Cisapride
• Dronedarone
• Mesoridazine
• Pimozide
• Piperaquine
• Saquinavir
• Sparfloxacin
• Terfenadine
• Thioridazine
• Ziprasidone

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Amiodarone
• Anagrelide
• Aripiprazole
• Aripiprazole Lauroxil
• Arsenic Trioxide
• Buserelin
• Clarithromycin
• Clozapine
• Crizotinib
• Dabrafenib
• Degarelix
• Delamanid
• Deslorelin
• Deutetrabenazine
• Domperidone
• Donepezil
• Efavirenz
• Escitalopram
• Fluconazole
• Fluoxetine
• Foscarnet
• Gonadorelin
• Goserelin
• Histrelin
• Hydroxychloroquine
• Hydroxyzine
• Ivabradine
• Ketoconazole
• Leuprolide
• Levofloxacin
• Methadone
• Metronidazole
• Moxifloxacin
• Nafarelin
• Ondansetron
• Panobinostat
• Pasireotide
• Pazopanib
• Pimavanserin
• Pitolisant
• Posaconazole
• Quetiapine
• Ribociclib
• Sevoflurane
• Sotalol
• Sulpiride
• Tacrolimus
• Triptorelin
• Vandetanib
• Vemurafenib
• Vinflunine
• Zuclopenthixol

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Blood or bone marrow problems (eg, cytopenia, neutropenia) or
• Congestive heart failure or
• Heart rhythm problems (eg, arrhythmias, QT prolongation) or
• Mineral imbalance (eg, low magnesium or potassium in the blood) or
• Nerve problems (eg, peripheral neuropathy)—Use with caution. May make these conditions worse. or

• Heart rhythm problem (eg, congenital long QT syndrome)—Eribulin injection should not be given in patients with this condition.

• Kidney disease or
• Liver disease—Use with caution. You may require a lower dose of this medicine. Talk with your doctor if you have concerns about this.

5.1 Neutropenia

In Study 1, severe neutropenia (ANC < 500/mm3) lasting more than one week occurred in 12% (62/503) of patients with metastatic breast cancer, leading to discontinuation in <1% of patients.  Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia [see Adverse Reactions (6.1)].

In Study 1, patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin > 1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.

In Study 2, severe neutropenia (ANC < 500/mm3) lasting more than one week occurred in 12% (26/222) of patients with liposarcoma or leiomyosarcoma. Febrile neutropenia occurred in 0.9% of patients treated with Halaven and fatal neutropenic sepsis in 0.9% [see Adverse Reactions (6.1)].

Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of Halaven and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days [see Dosage and Administration (2.2)]. Clinical studies of Halaven did not include patients with baseline neutrophil counts below 1,500/mm3.

5.2 Peripheral Neuropathy

In Study 1, Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients with metastatic breast cancer (MBC). Peripheral neuropathy was the most common toxicity leading to discontinuation of Halaven (5% of patients; 24/503) in Study 1.  Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days).

In Study 2, Grade 3 peripheral neuropathy occurred in 3.1% (7/223) of Halaven-treated patients. Peripheral neuropathy led to discontinuation of Halaven in 0.9% of patients. The median time to first occurrence of peripheral neuropathy of any severity was 5 months (range: 3.5 months to 9 months).  Neuropathy lasting more than 60 days occurred in 58% (38/65) of patients.  Sixty three percent (41/65) had not recovered within a median follow-up duration of 6.4 months (range: 27 days to 29 months).

Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold Halaven in patients who experience Grade 3 or 4 peripheral neuropathy, until resolution to Grade 2 or less [see Dosage and Administration (2.2)].

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.

8.1 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 [see Clinical Pharmacology (12.1)]. 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 [see Data].  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 2% to 4% and 15% to 20%, 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 0.04, 0.13, 0.43 and 0.64 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/m2 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.

8.2 Lactation

Risk Summary

There is no information regarding the presence of eribulin mesylate or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. No lactation studies in animals were conducted.  Because of the potential for serious adverse reactions in breastfed infants from eribulin mesylate, advise women not to breastfeed during treatment with Halaven and for 2 weeks after the final dose.

8.3 Females and Males of Reproductive Potential

Contraception

Females

Based on findings from an animal reproduction study and its mechanism of action, Halaven can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].  Advise females of reproductive potential to use effective contraception during treatment with Halaven and for at least 2 weeks following the final dose.

Males

Based on its mechanism of action, 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.

Infertility 

Males 

Based on animal data, Halaven may result in damage to male reproductive tissues leading to impaired fertility of unknown duration [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of Halaven in pediatric patients below the age of 18 years have not been established.

8.5 Geriatric Use

Study 1 did not include sufficient numbers of subjects with metastatic breast cancer aged 65 years and older to determine whether they respond differently from younger subjects. Of the 827 subjects who received the recommended dose and schedule of Halaven in clinical studies with advanced breast cancer, 15% (121/827) were 65 and older, and 2% (17/827) patients were 75 and older. No overall differences in safety were observed between these subjects and younger subjects.

Clinical studies of Halaven did not include a sufficient number of subjects in Study 2 aged 65 years and older to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment

Administration of Halaven at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). Halaven was not studied in patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)]. 

8.7 Renal Impairment

For patients with moderate or severe renal impairment (CLcr 15-49 mL/min), reduce the starting dose to 1.1 mg/m2 [see Dosage and Administration (2.1), Clinical Pharmacology (12.3)].

You should not use Halaven if you are allergic to eribulin.

To make sure Halaven is safe for you, tell your doctor if you have:

• liver disease;

• kidney disease;

• heart disease;

• peripheral vascular disease such as Raynaud's syndrome;

• personal or family history of long QT syndrome; or

• an electrolyte imbalance (such as low levels of potassium or magnesium in your blood).

Do not use Halaven if you are pregnant. It could harm the unborn baby. Use effective birth control to prevent pregnancy while using Halaven, and for at least 2 weeks after your last dose.

If a man fathers a baby while using eribulin, the baby may have birth defects. Use condoms to prevent pregnancy during your treatment, and for at least 14 weeks (3.5 months) after your last dose.

It is not known whether eribulin passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using Halaven.

Applies to eribulin: intravenous solution

Along with its needed effects, eribulin (the active ingredient contained in Halaven) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur while taking eribulin:

• Black, tarry stools
• bladder pain
• bloating or swelling of the face, arms, hands, lower legs, or feet
• bloody or cloudy urine
• body aches or pain
• burning, numbness, tingling, or painful sensations
• chills
• convulsions
• cough
• decreased urine
• decreased weight
• difficult or labored breathing
• difficult, burning, or painful urination
• dry mouth
• ear congestion
• fever
• frequent urge to urinate
• headache
• increased thirst
• irregular heartbeat
• loss of appetite
• loss of voice
• lower back or side pain
• mood changes
• muscle pain or cramps
• nasal congestion
• nausea or vomiting
• numbness or tingling in the hands, feet, or lips
• pale skin
• rapid weight gain
• runny nose
• sneezing
• sore throat
• tightness in the chest
• troubled breathing with exertion
• ulcers, sores, or white spots in the mouth
• unsteadiness or awkwardness
• unusual bleeding or bruising
• unusual tiredness or weakness
• unusual weight gain or loss
• weakness in the arms, hands, legs, or feet

• Fainting
• irregular heartbeat, recurrent

Some side effects of eribulin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• back pain
• belching
• bone pain
• change in taste
• cracked lips
• depression
• diarrhea
• difficulty having a bowel movement (stool)
• difficulty with moving
• difficulty with swallowing
• dizziness
• hair loss or thinning of the hair
• heartburn
• indigestion
• lack or loss of strength
• loss of taste
• muscle spasm or weakness
• muscle stiffness
• pain in the arms or legs
• pain in the joints
• rash
• sores, ulcers, or white spots on the lips, tongue, or inside the mouth
• stomach discomfort, upset, or pain
• swelling or inflammation of the mouth
• trouble sleeping
• watering of the eyes
• weight loss

Applies to eribulin: intravenous solution

Hematologic

Very common (10% or more): Neutropenia (up to 82%), anemia (up to 58%)
Very common (10% or more): Urinary tract infection (up to 10%)
Uncommon (0.1% to 1%): Dysuria, hematuria, proteinuria, hematuria, leukopenia, lymphopenia[Ref]

In one study, grade 3 neutropenia occurred in 28% of patients, 29% experience grade 4 neutropenia, and 5% of patients experienced febrile neutropenia. Dose reductions due to neutropenia occurred in 12% of patients and discontinuation was required in less than 1% of patients. Grade 3 or greater thrombocytopenia was reported in 1% of patients. Granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor was used in 19% of patients treated with this drug.[Ref]

Nervous system

Very common (10% or more): Peripheral neuropathy (up to 35%)
Common (1% to 10%): Dysgeusia, dizziness, hypoesthesia, lethargy, neurotoxicity, polyneuropathy, peripheral sensory neuropathy, paresthesia[Ref]

Gastrointestinal

Very common (10% or more): Nausea (up to 35%), constipation (up to 25%), diarrhea (up to 18%), vomiting (up to 18%)
Common (1% to 10%): Abdominal pain, stomatitis, dry mouth, dyspepsia, gastroesophageal reflux disease, mouth ulceration, mucosal inflammation, abdominal distension
Postmarketing reports: Pancreatitis[Ref]

Cardiovascular

Common (1% to 10%): QT prolongation, tachycardia, peripheral edema[Ref]

Dermatologic

Very common (10% or more): Alopecia (up to 45%)
Common (1% to 10%): Rash, pruritus, nail disorder, night sweats, palmar plantar erythrodysesthesia, dry skin, erythema, hyperhidrosis[Ref]

Genitourinary

Very common (10% or more): Urinary tract infection (up to 10%)
Uncommon (0.1% to 1%): Dysuria, hematuria, proteinuria

v[Ref]

Hepatic

Common (1% to 10%): Alanine aminotransferase increased, aspartate aminotransferase increased, gamma glutamyl transferase increased, hyperbilirubinemia[Ref]

Metabolic

Very common (10% or more): Weight decreased (up to 21%), anorexia (up to 20%)
Common (1% to 10%): Hypokalemia[Ref]

Musculoskeletal

Very common (10% or more): Arthralgia/Myalgia (up to 22%), back pain (up to 16%), bone pain (up to 12%), pain in extremity (up to 11%)
Common (1% to 10%): Muscle spasms, musculoskeletal pain, musculoskeletal chest pain[Ref]

Ocular

Common (1% to 10%): Lacrimation increased, conjunctivitis[Ref]

Other

Very common (10% or more): Asthenia/Fatigue (up to 54%), pyrexia (up to 21%)
Common (1% to 10%): Disseminated intravascular coagulation, oral herpes, mucosal inflammation, hot flushes, pain, chills, peripheral neuropathy, headache
Frequency not reported: Tinnitus[Ref]

Psychiatric

Very common (10% or more): Headache
Common (1% to 10%): Insomnia, depression[Ref]

Respiratory

Very common (10% or more): Dyspnea (up to 16%), cough (up to 14%)
Rare (less than 0.1%): Upper respiratory tract infection, nasopharyngitis, rhinitis
Frequency not reported: Oropharyngeal pain, epistaxis, rhinorrhea[Ref]

Immunologic

Very common (10% or more):
Common (1% to 10%): Oral candidiasis, influenza-like illness, mucosal inflammation
Postmarketing reports: Pneumonia, sepsis/neutropenic sepsis[Ref]

Some side effects of Halaven may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.