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Eflornithine (Monograph)

Brand name: Iwilfin
Drug class: Antineoplastic Agents

Introduction

Eflornithine hydrochloride, an ornithine decarboxylase inhibitor, is an antineoplastic agent.

Uses for Eflornithine

Eflornithine hydrochloride has the following uses:

Eflornithine hydrochloride is indicated to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma (HRNB) who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy.

Eflornithine Dosage and Administration

General

Eflornithine hydrochloride is available in the following dosage form(s) and strength(s):

Tablets: 192 mg (of eflornithine)

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Prior to initiation of eflornithine, perform baseline audiogram, complete blood count, and liver function tests.

Eflornithine is taken orally twice daily with or without food until disease progression, unacceptable toxicity, or for a maximum of 2 years.

Eflornithine tablets may be swallowed whole, chewed, or crushed and mixed with soft food or liquid.

Pediatric Patients

Adults

Detailed Eflornithine topical dosage information

Cautions for Eflornithine

Contraindications

None.

Warnings/Precautions

Myelosuppression

Eflornithine can cause myelosuppression. In the pooled safety population, Grade 3 or 4 neutropenia occurred in 4.2% of patients. Febrile neutropenia occurred in 0.6% of patients. Bone marrow failure occurred in 1 patient. Grade 3 or 4 thrombocytopenia occurred in 1.4% of patients. Grade 3 anemia occurred in 3.3% of patients.

Perform blood counts including neutrophil count, platelet count, and hemoglobin level prior to administration of eflornithine and periodically during treatment. Withhold, reduce the dose, or permanently discontinue the drug based on severity.

Hepatotoxicity

Eflornithine can cause hepatotoxicity. In the pooled safety population, Grade 3 or 4 events of increased alanine aminotransferase (ALT) occurred in 11% of patients. Grade 3 or 4 events of increased aspartate aminotransferase (AST) occurred in 6% of patients. Grade 3 or 4 events of increased bilirubin occurred in 0.3% of patients. Increased ALT/AST leading to dose interruption or reduction occurred in 2.5% of patients. Eflornithine was discontinued due to increased ALT/AST in 0.6% of patients.

Perform liver function tests (ALT, AST, and total bilirubin) prior to the start of eflornithine, every month for the first 6 months of treatment, then once every 3 months or as clinically indicated, with more frequent testing in patients who develop transaminase or bilirubin elevations. Withhold and reduce the dose or permanently discontinue therapy based on severity.

Hearing Loss

Eflornithine can cause hearing loss. In the pooled safety population, 81% of patients had an abnormal audiogram at baseline. New or worsening hearing loss occurred in 13% of patients who received eflornithine; hearing loss worsened from baseline to Grade 3 or 4 in 12% of patients. Tinnitus occurred in 1 patient. Hearing loss leading to dose interruption or reduction occurred in 4% of patients. New or worsening hearing loss requiring new use of hearing aids occurred in 7% of patients. Eflornithine was discontinued due to hearing loss in 1.4% of patients. Among all patients with new or worsening hearing loss during eflornithine treatment, the hearing loss resolved to baseline in 9% of patients. Among 18 patients who experienced new or worsening hearing loss and had dose modifications, 67% (N=12) improved or resolved to baseline.

Perform audiogram prior to initiation of therapy and at 6 month intervals, or as clinically indicated, to monitor for potential hearing loss. Withhold and reduce the dose or permanently discontinue therapy based on severity.

Embryo-fetal Toxicity

Based on findings from animal studies and its mechanism of action, eflornithine can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of eflornithine to pregnant rats and rabbits during the period of organogenesis resulted in embryolethality at doses equivalent to the recommended human dose.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with eflornithine and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with eflornithine and for 1 week after the last dose.

Specific Populations

Pregnancy

Based on findings from animal studies and its mechanism of action, eflornithine can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of eflornithine to pregnant rats and rabbits during the period of organogenesis resulted in embryolethality at doses equivalent to the recommended human dose. There are no available data on the use of eflornithine in pregnant women. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

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.

In an embryo-fetal development study, once daily oral administration of 30, 80 or 200 mg/kg/day eflornithine to pregnant rats during the period of organogenesis (gestation day 6 to 7) resulted in reduced fetal body weights and an increase in the incidence of skeletal variations (presence of a 14th rudimentary rib, 14th full rib, 27th presacral vertebrae) at 200 mg/kg/day [approximately 0.8 to 2 times the recommended human dose of 1152 ± 384 mg/m2/day based on body surface area (BSA)]. In a dose range-finding embryo-fetal development study, pregnant rats receiving oral administration of up to 2000 mg/kg/day eflornithine during the period of organogenesis exhibited increased early resorptions and post-implantation loss beginning at 300 mg/kg/day (approximately 1 to 2 times the recommended human dose of 1152 ± 384 mg/m2/day based on BSA), with 100% post-implantation loss and no viable fetuses at ≥800 mg/kg/day (approximately ≥3 to 6 times the recommended human dose of 1152 ± 384 mg/m2/day based on BSA).

In an embryo-fetal development study in rabbits, once daily oral administration of 15, 45 or 135 mg/kg/day eflornithine to pregnant animals during the period of organogenesis (gestation day 7 to 20) resulted in reduced gravid uterine weight accompanied by increased pre-implantation and post-implantation loss, increased early resorptions, and reduced fetal body weights at 135 mg/kg/day (approximately 1 to 2 times the recommended human dose of 1152 ± 384 mg/m2/day based on BSA). Eflornithine resulted in abortions in one animal at 15 mg/kg/day (approximately 0.1 to 0.2 times the recommended human dose of 1152 ± 384 mg/m2/day based on BSA) and one animal at 135 mg/kg/day. In a dose range-finding embryo-fetal development study, pregnant rabbits receiving oral administration of up to 500 mg/kg/day eflornithine during the period of organogenesis exhibited 100% post-implantation loss and no viable fetuses at 500 mg/kg/day (approximately 4 to 8 times the recommended human dose of 1152 ± 384 mg/m2/day based on BSA). There was no clear evidence of eflornithine-related fetal malformations in rats or rabbits.

Lactation

There are no data on the presence of eflornithine in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with eflornithine and for 1 week after the last dose.

Females and Males of Reproductive Potential

Based on animal data and its mechanism of action, eflornithine can cause fetal harm when administered to a pregnant woman.

Verify pregnancy status in females of reproductive potential prior to initiating eflornithine hydrochloride.

Advise females of reproductive potential to use effective contraception during treatment with eflornithine and for 1 week after the last dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with eflornithine and for 1 week after the last dose.

Pediatric Use

The safety and effectiveness of eflornithine have been established to reduce the risk of relapse in pediatric patients with high-risk neuroblastoma (HRNB) who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy. Use of eflornithine for this indication is supported by evidence from adequate and well-controlled studies in pediatric patients with a median age of 4 years (range: 1 to 17).

The safety and effectiveness of eflornithine have not been established in pediatric patients for other indications.

Common Adverse Effects

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Eflornithine is an irreversible inhibitor of the enzyme ornithine decarboxylase (ODC), the first and rate-limiting enzyme in the biosynthesis of polyamines and a transcriptional target of MYCN. Polyamines are involved in differentiation and proliferation of mammalian cells and are important for neoplastic transformation. Inhibition of polyamine synthesis by eflornithine restored the balance of the LIN28/Let-7 metabolic pathway, which is involved in regulation of cancer stem cells and glycolytic metabolism, by decreasing expression of the oncogenic drivers MYCN and LIN28B in MYCN-amplified neuroblastoma. In vitro, eflornithine induced senescence and suppressed neurosphere formation in MYCN-amplified and MYCN non-amplified neuroblastoma cells, indicating a cytostatic effect. Treatment with eflornithine prevented or delayed tumor formation in mice injected with limiting dilutions of MYCN-amplified neuroblastoma cells.

Advice to Patients

Additional Information

AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Eflornithine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

192 mg (of eflornithine)

Iwilfin

US WorldMeds

AHFS DI Essentials™. © Copyright 2024, Selected Revisions March 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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