Halaven (Page 3 of 7)

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

7 DRUG INTERACTIONS

7.1 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) [see Clinical Pharmacology (12.3)].

7.2 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 [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

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)] .

10 OVERDOSAGE

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.

11 DESCRIPTION

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 okad ai. The chemical name for eribulin mesylate is 11,15:18,21:24,28-Triepoxy-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)-3-amino-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 C40 H59 NO11 •CH4 O3 S. Eribulin mesylate has the following structural formula:

a product isolated from the marine sponge Halichondria okadai.  The chemical name for eribulin mesylate is 11,15:18,21:24,28-Triepoxy-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)-3-amino-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:
(click image for full-size original)

HALAVEN is a clear, colorless, sterile solution for intravenous administration. Each single-dose vial contains 1 mg of eribulin mesylate in 2 mL of solution. Each mL of solution contains 0.5 mg of eribulin mesylate (equivalent to 0.44 mg eribulin) in dehydrated alcohol (5% v/v) and water for injection (95% v/v). Sodium hydroxide or hydrochloric acid may be used for pH adjustment.

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