Eflornithine Hydrochloride (Monograph)

Brand name: Iwilfin
Drug class: Antineoplastic Agents

Introduction

Ornithine decarboxylase inhibitor; antineoplastic agent.

Uses for Eflornithine Hydrochloride

High-risk Neuroblastoma

Used to reduce risk of relapse in adult and pediatric patients with high-risk neuroblastoma who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy; designated an orphan drug by FDA for this use.

Eflornithine Hydrochloride Dosage and Administration

General

Pretreatment Screening

Obtain CBC, liver function tests, and baseline audiogram prior to initiation.
Verify pregnancy status in females of reproductive potential.

Patient Monitoring

Monitor blood counts including neutrophil count, platelet count, and hemoglobin level periodically during treatment.
Perform liver function tests (ALT, AST, and total bilirubin) every month for first 6 months, then once every 3 months or as clinically indicated, with more frequent testing in patients who develop aminotransferase or bilirubin elevations.
Perform audiogram at 6-month intervals, or as clinically indicated, to monitor for potential hearing loss.

Administration

Administer orally, with or without food.

Can be swallowed whole, chewed, or crushed and mixed with 2 tablespoons of soft food or liquid. If crushed, visually confirm entire contents are consumed. If any crushed tablet particles remain in container, mix with an additional small volume (no more than 1 ounce or 30 mL) of soft food or liquid. Crushed tablet preparation should be discarded after 1 hour.

A missed dose should be administered as soon as possible. If next dose is due within 7 hours, missed dose should be skipped.

If vomiting occurs after taking, additional dose should not be administered; continue with next scheduled dose.

Dosage

Pediatric Patients

High-risk Neuroblastoma

Oral

Recommended dosage is based on body surface area (BSA) as listed in Table 1. Recalculate BSA dosage every 3 months during treatment. Administer treatment for 2 years or until recurrence of disease or unacceptable toxicity.

Table 1. Recommended Eflornithine Oral Dosage Based on Body Surface Area1
Body Surface Area (m²)	Oral Dosage
>1.5	768 mg (4 tablets) twice daily
0.75 to 1.5	576 mg (3 tablets) twice daily
0.5 to <0.75	384 mg (2 tablets) twice daily
0.25 to <0.5	192 mg (1 tablet) twice daily

Adults

High-risk Neuroblastoma

Oral

Recommended dosage is based on BSA as listed in Table 1. Administer treatment for 2 years or until recurrence of disease or unacceptable toxicity.

Dosage Modification for Toxicity

Recommended dosage modifications for adverse reactions in both adult and pediatric patients are provided in Tables 2 and 3. If subsequent adverse reactions occur, continue dosage reduction until reaching minimum dosage of 192 mg orally once per day. Permanently discontinue if unable to tolerate minimum dosage of 192 mg once per day.

Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

Table 2. Recommended Actions for Eflornithine Adverse Reactions1
Adverse Reaction	Severity	Dosage Modification
Neutrophil count decreased	<500/mm³	Withhold until recovery to ≥500/mm³. If recovered within 7 days, resume at same dosage. If recovered after 7 days, resume at next reduced dosage level (Table 3).
Platelet count decreased	<25,000/mm³	Withhold until recovery to ≥25,000/mm³. If recovered within 7 days, resume at same dosage. If recovered between 7 and 14 days, resume at next reduced dosage level (Table 3). If not recovered within 14 days, permanently discontinue.
Anemia	<8 g/dL	Withhold until hemoglobin recovery to ≥8 g/dL, then resume at same dosage. If anemia recurs (hemoglobin <8 g/dL), withhold until recovery to ≥8 g/dL and resume at next reduced dosage level (Table 3).
Hepatotoxicity (AST or ALT increased)	AST or ALT ≥10 times the ULN	Withhold until recovery to <10 times ULN. If recovered within 7 days, resume at same dosage. If recovered after 7 days, resume at next reduced dosage level (Table 3).
Hearing loss	Clinically concerning new or worsening hearing loss compared to eflornithine baseline audiogram	Continue dosing and repeat audiogram in 3 weeks. If improved, continue at same dosage. If clinically concerning changes persist, hold for up to 30 days and repeat audiogram. If stable or improved, resume at next reduced dosage level (Table 3).
Nausea, vomiting, or diarrhea	Grade 3	If symptoms respond to supportive treatment (e.g., anti-emetic, anti-diarrheal therapy), continue at same dosage. If symptoms do not respond to treatment, withhold until recovery to ≤ Grade 2. Resume at next reduced dosage level (Table 3).
Other adverse reactions	Grade 3 or 4	Withhold until recovery to ≤ Grade 2. Resume at next reduced dosage level (Table 3).
Other adverse reactions	Recurrent Grade 4	Permanently discontinue.

Table 3. Recommended Eflornithine Oral Dosage Reduction for Toxicity Management1
Current Dosage	Reduced Dosage
768 mg (4 tablets) twice daily	576 mg (3 tablets) twice daily
576 mg (3 tablets) twice daily	384 mg (2 tablets) twice daily
384 mg (2 tablets) twice daily	192 mg (1 tablet) twice daily
192 mg (1 tablet) twice daily	192 mg (1 tablet) once daily

Special Populations

Hepatic Impairment

No specific population dosage recommendations at this time.

Renal Impairment

No specific population dosage recommendations at this time.

Geriatric Patients

No specific population dosage recommendations at this time.

Cautions for Eflornithine Hydrochloride

Contraindications

None.

Warnings/Precautions

Myelosuppression

Can cause myelosuppression.

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

Hepatotoxicity

Can cause hepatotoxicity.

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

Hearing Loss

Can cause hearing loss.

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 dosage or permanently discontinue based on severity.

Embryo-fetal Toxicity

Based on animal studies and mechanism of action, can cause fetal harm.

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.

Specific Populations

Pregnancy

Based on findings from animal studies and mechanism of action, 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. No available data on use of eflornithine in pregnant women. Advise pregnant women and females of reproductive potential of potential risk to a fetus.

Lactation

No data on presence of eflornithine in human milk, effects on breast-fed child, or effects on milk production. Because of potential for serious adverse reactions in breast-fed children, advise women not to breastfeed during treatment and for 1 week after last dose.

Females and Males of Reproductive Potential

Based on animal data and 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 therapy.

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

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

Pediatric Use

Safety and effectiveness established in pediatric patients with high-risk neuroblastoma; pediatric patients 1–17 years of age (median 4 years) included in clinical studies.

Safety and effectiveness not established in pediatric patients for other indications.

Renal Impairment

No studies conducted in patients with renal impairment.

Common Adverse Effects

Most common adverse effects (≥5%): hearing loss, otitis media, pyrexia, pneumonia, diarrhea.

Most common Grade 3 or 4 laboratory abnormalities (≥2%): increased ALT, increased AST, decreased neutrophil count, decreased hemoglobin.

Drug Interactions

Does not induce or inhibit any CYP enzymes or act as a substrate or inhibitor of major drug transporters; no clinically relevant drug interactions.

Eflornithine Hydrochloride Pharmacokinetics

Absorption

Onset

Peak plasma concentrations (C_max) achieved 3.5 hours post dosing.

Effect of Food

C_maxand AUC not affected by food (high fat and high calories).

Administration of crushed tablets in standard pudding admixture: no effect on exposure.

Distribution

Plasma Protein Binding

Does not specifically bind to human plasma proteins.

Elimination

Metabolism

Not highly metabolized.

Elimination Route

80% excreted unchanged in the urine.

Half-life

Terminal plasma elimination half-life: 3.5 hours.

Special Populations

Age (range: 1 to 19 years), sex, or BSA (range: 0.4 to 2 m²) and mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin <1 times ULN and any AST): no clinically meaningful effects on exposure.

Stability

Storage

Oral

Tablets

Store at 20–25ºC, with excursions permitted between 15–30°C.

Actions

Irreversible inhibitor of ornithine decarboxylase, the first and rate-limiting enzyme in 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 restores 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 MYCNnon-amplified neuroblastoma cells, indicating a cytostatic effect.
Prevention or delayed tumor formation observed in mice models of MYCN-amplified neuroblastoma.

Advice to Patients

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information).
Inform patients and caregivers of the risk of bone marrow suppression and to promptly report any signs or symptoms of thrombocytopenia, anemia, or infection.
Inform patients and caregivers of the risk of hepatotoxicity and to promptly report any signs or symptoms of hepatotoxicity.
Inform patients and caregivers of the risk of hearing loss, and to promptly report any signs or symptoms of new or worsening hearing loss.
Inform patients and caregivers that eflornithine can be harmful to a developing fetus and cause loss of pregnancy. 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.
Advise women not to breastfeed during treatment with eflornithine and for 1 week after the last dose.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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

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