April 23, 2017
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Halaven

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Halaven Injection




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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].

In Study 1, patients with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x 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 x 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].

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]. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm³ .

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].

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].

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.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Neutropenia

Advise patients to contact their health care provider for a fever of 100.5°F or greater or other signs or symptoms of infection such as chills, cough, or burning or pain on urination [see WARNINGS AND PRECAUTIONS].

Peripheral Neuropathy

Advise patients to inform their healthcare providers of new or worsening numbness, tingling and pain in their extremities [see WARNINGS AND PRECAUTIONS].

Embryo-Fetal Toxicity
  • Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS, Use in Specific Populations].
  • Advise females of reproductive potential to use effective contraception during treatment with HALAVEN and for at least 2 weeks after the final dose [see Use in Specific Populations].
  • 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].
Lactation

Advise women not to breastfeed during treatment with HALAVEN and for 2 weeks after the final dose [see Use in Specific Populations]

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been conducted with eribulin mesylate. Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay.

Fertility studies have not been conducted with eribulin mesylate in humans or animals; however, nonclinical findings in repeat-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (based on body surface area) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (based on body surface area) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (based on body surface area) weekly for 3 out of 5 weeks, repeated for 6 cycles.

Use In Specific Populations

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]. 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.

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.

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]. 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].

Pediatric Use

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

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.

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, CLINICAL PHARMACOLOGY].

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, CLINICAL PHARMACOLOGY].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 11/8/2016

Warnings
Precautions

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