Eflornithine hydrochloride, an ornithine decarboxylase inhibitor, is an antineoplastic agent.1
Eflornithine hydrochloride is used to reduce the 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.1 Eflornithine has been designated an orphan drug by FDA for this use.2
The efficacy of eflornithine is based on an externally controlled comparative analysis of 2 trials (Study 3b, which served as the investigational arm, and Study ANBL0032, which served as a clinical trial-derived external control arm).1, 3, 4
Study 3b was a multicenter, open-label, nonrandomized trial in pediatric patients with high-risk neuroblastoma who completed standard of care up-front therapy including immunotherapy.1, 5 The study consisted of two cohorts.1, 3 The primary efficacy data for the experimental arm of the comparative analysis was derived from one of the cohorts (Stratum 1), which consisted of patients who were in remission at the end of up-front therapy; these patients demonstrated at least a partial response to prior multiagent, multimodality therapy, including induction, consolidation, and anti-GD2 immunotherapy.1, 3 Stratum 1 enrolled a total of 105 eligible patients; these patients received eflornithine orally twice daily, dosed based on body surface area (BSA) until disease progression, unacceptable toxicity, or for a maximum of 2 years.1 Following completion of eflornithine therapy, patients were followed for a total duration of 7 years.1, 3 The major efficacy outcome was event-free survival, defined as disease progression, relapse, secondary cancer, or death due to any cause.1, 3 An additional efficacy outcome measure was overall survival, defined as death due to any cause.1, 3 Study 3b was prospectively designed to compare outcomes to the historical event-free survival rate from Study ANBL0032 reported in the published literature.1
The external comparator control arm was derived from 1,241 patients in the experimental arm of Study ANBL0032, which was a multicenter, open-label, randomized trial comparing combination therapy with dinutuximab, granulocyte-macrophage colony-stimulating factor (G-CSF), interleukin-2, and cis-retinoic acid to cis-retinoic acid alone in pediatric patients with high-risk neuroblastoma previously treated with induction and consolidation therapy who demonstrated at least a partial response.1, 4
The efficacy population for the comparative analysis of Study 3b and ANBL0032 included patients from both studies who were younger than 21 years of age with histologic verification of high-risk neuroblastoma and who demonstrated at least a partial response based on imaging, with no evidence of disease in the bone marrow, at the end of immunotherapy; patients in the efficacy population also did not experience an event-free survival event prior to starting eflornithine maintenance therapy (for Study 3b), or for at least 30 days from the end of immunotherapy (for Study ANBL0032).1 Eligible patients in Study 3b received immunotherapy in Study ANBL0032 or were treated off study according to the ANBL0032 study protocol.1 Patients who met criteria for the comparison and had complete data for specified clinical covariates were matched 1:3 (eflornithine:no eflornithine) using propensity scores.1, 4
The matched efficacy populations for the primary analysis included 90 patients treated with eflornithine and 270 control patients from Study ANBL0032.1, 4 The majority of patients were male (59%) and white (88%).1 The median age at diagnosis was 3 years; the majority (86%) of patients had Stage 4 disease and MYCN amplification was observed in 44% of tumors.1 At the end of immunotherapy, 87% of patients had a complete response, 8% had a very good partial response, and 5% had a partial response.1 In the protocol-specific primary analysis, the 4-year event-free survival was 84% in the eflornithine group and 73% in the non-eflornithine group.4 Overall survival comparisons also favored eflornithine, with 4-year overall survival rates of 96% in the eflornithine group and 84% in the non-eflornithine group.4 Given the uncertainty in treatment effect estimation associated with the externally controlled study design, supplementary analyses in subpopulations or using alternative statistical methods were performed.1 In these analyses, the event-free survival hazard ratio ranged from 0.43—0.59 and the overall survival hazard ratio ranged from 0.29—0.45 in favor of eflornithine.1
Eflornithine is administered orally as tablets, with or without food.1
Eflornithine tablets can be swallowed whole, chewed, or crushed.1
For patients who have difficulty swallowing tablets, eflornithine can be chewed or crushed and mixed with 2 tablespoons of soft food or liquid.1 Visually confirm that the entire contents are consumed.1 If any crushed tablet particles remain in the container, mix with an additional small volume (no more than 1 ounce or 30 mL) of soft food or liquid.1 The crushed tablet preparation should be discarded after 1 hour.1
A missed dose of eflornithine should be administered as soon as possible.1 If the next dose is due within 7 hours, the missed dose should be skipped.1
If vomiting occurs after taking eflornithine, an additional dose should not be administered; continue with the next scheduled dose.1
Store eflornithine tablets at 20 to 25°C, with excursions permitted between 15 to 30°C.1
Available as eflornithine hydrochloride; dosage is expressed in terms of eflornithine.1
The recommended dosage of eflornithine is based on body surface area (BSA) as listed in Table 1.1 Recalculate the BSA dosage every 3 months during treatment with eflornithine.1 Administer treatment for a maximum of 2 years or until recurrence of disease or unacceptable toxicity.1
Dosage Modification for Toxicity
The recommended eflornithine dosage modifications for adverse reactions are provided below in Tables 2 and 3.1 If subsequent adverse reactions occur, continue dosage reduction until reaching the minimum dosage of 192 mg orally once per day.1 Permanently discontinue eflornithine if the patient is unable to tolerate the minimum dosage of 192 mg once per day.1
Adverse Reaction | Severitya | Dosage Modification |
|---|---|---|
Neutrophil count decreased | <500/mm3 | Withhold eflornithine until recovery to ≥500/mm3.1 If recovered within 7 days, resume eflornithine at the same dosage.1 If recovered after 7 days, resume eflornithine at the next reduced dosage level (Table 3).1 |
Platelet count decreased | <25,000/mm3 | Withhold eflornithine until recovery to ≥25,000/mm3.1 If recovered within 7 days, resume eflornithine at the same dosage.1 If recovered between 7 and 14 days, resume eflornithine at the next reduced dosage level (Table 3).1 If not recovered within 14 days, permanently discontinue eflornithine.1 |
Anemia | <8 g/dL | Withhold eflornithine until hemoglobin recovery to ≥8 g/dL, then resume eflornithine at the same dosage.1 If anemia recurs (hemoglobin <8 g/dL), withhold eflornithine until recovery to ≥8 g/dL and resume eflornithine at the next reduced dosage level (Table 3).1 |
Hepatotoxicity (AST or ALT increased) | AST or ALT ≥10 times the upper limit of normal (ULN) | Withhold eflornithine until recovery to <10 times ULN.1 If recovered within 7 days, resume eflornithine at the same dosage.1 If recovered after 7 days, resume eflornithine at the next reduced dosage level (Table 3).1 |
Hearing loss | Clinically concerning new or worsening hearing loss compared to baseline audiogram | Continue dosing with eflornithine and repeat audiogram in 3 weeks.1 If improved, continue eflornithine at the same dosage.1 If clinically concerning changes persist, hold eflornithine for up to 30 days and repeat audiogram.1 If stable or improved, resume eflornithine at the next reduced dosage level (Table 3).1 |
Nausea, vomiting, or diarrhea | Grade 3 | If symptoms respond to supportive treatment (e.g., anti-emetic, anti-diarrheal therapy), continue eflornithine at the same dosage.1 If symptoms do not respond to treatment, withhold eflornithine until recovery to ≤Grade 2.1 Resume eflornithine at the next reduced dosage level (Table 3).1 |
Other adverse reactions | Grade 3 or 4 | Withhold eflornithine until recovery to ≤Grade 2.1 Resume eflornithine at the next reduced dosage level (Table 3).1 |
Other adverse reactions | Recurrent Grade 4 | Permanently discontinue eflornithine.1 |
aSeverity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.1
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 |
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
For patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/min), the recommended dose should be reduced by 50% (see Table 4).1
Body Surface Area (m2) | Recommended Dosage |
|---|---|
>1.5 | 384 mg (2 tablets) twice daily |
0.75 to 1.5 | 384 mg (2 tablets) in the morning and 192 mg (1 tablet) in the evening |
0.5 to < 0.75 | 192 mg (1 tablet) twice daily |
0.25 to <0.5 | 192 mg (1 tablet) once daily |
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Eflornithine can cause myelosuppression.1
In the pooled safety population, Grade 3 or 4 neutropenia occurred in 4.2% of patients who received eflornithine.1 Febrile neutropenia occurred in 0.6% of patients.1 Bone marrow failure occurred in 1 patient.1 Grade 3 or 4 thrombocytopenia occurred in 1.4% of patients.1 Grade 3 anemia occurred in 3.3% of patients.1
Perform blood counts including neutrophil count, platelet count, and hemoglobin level prior to administration of eflornithine and periodically during treatment.1 Withhold, reduce the dosage, or permanently discontinue eflornithine based on severity.1
Eflornithine can cause hepatotoxicity.1
In the pooled safety population, Grade 3 or 4 events of increased ALT occurred in 11% of patients who received eflornithine.1 Grade 3 or 4 events of increased AST occurred in 6% of patients.1 Grade 3 or 4 events of increased bilirubin occurred in 0.3% of patients.1 Increased ALT/AST resulted in dose interruption or reduction in 2.5% of patients.1 Eflornithine was discontinued due to increased ALT/AST in 0.6% of patients.1
Perform liver function tests (ALT, AST, and total bilirubin) prior to initiating eflornithine, every month for the first 6 months of treatment, then once every 3 months or as clinically indicated; more frequent testing is recommended in patients who develop aminotransferase or bilirubin elevations.1 Withhold and reduce the dosage or permanently discontinue eflornithine based on severity.1
Eflornithine can cause hearing loss.1
In the pooled safety population, 81% of patients had an abnormal audiogram at baseline.1 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.1 Tinnitus occurred in 1 patient.1 Hearing loss resulted in dose interruption or reduction in 4% of patients.1 New or worsening hearing loss requiring new use of hearing aids occurred in 7% of patients.1 Eflornithine was discontinued due to hearing loss in 1.4% of patients.1 Among all patients with new or worsening hearing loss during eflornithine treatment, the hearing loss resolved to baseline in 9% of patients.1 Among 18 patients who experienced new or worsening hearing loss and had dose modifications, 67% (12 patients) improved or resolved to baseline.1
Monitor patients for potential hearing loss by performing an audiogram prior to initiation of eflornithine therapy and at 6-month intervals, or as clinically indicated.1 Withhold and reduce the dosage or permanently discontinue eflornithine based on severity.1
Based on findings from animal studies and its mechanism of action, eflornithine can cause fetal harm when administered to a pregnant woman.1
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.1
Advise pregnant women and females of reproductive potential of the potential risk to a fetus.1 Advise females of reproductive potential to use effective contraception during treatment with eflornithine and for 1 week after the last dose.1 Advise males with female partners of reproductive potential to use effective contraception during treatment with eflornithine and for 1 week after the last dose.1
Based on findings from animal studies and its mechanism of action, eflornithine can cause fetal harm when administered to a pregnant woman.1 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.1 There are no available data on the use of eflornithine in pregnant women.1 Advise pregnant women and females of reproductive potential of the potential risk to a fetus.1
There are no data on the presence of eflornithine in human milk, the effects on the breast-fed child, or the effects on milk production.1 Because of the potential for serious adverse reactions in breast-fed children, advise women not to breastfeed during treatment with eflornithine and for 1 week after the last dose.1
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.1 Verify pregnancy status in females of reproductive potential prior to initiating eflornithine.1
Advise females of reproductive potential to use effective contraception during treatment with eflornithine and for 1 week after the last dose.1
Advise males with female partners of reproductive potential to use effective contraception during treatment with eflornithine and for 1 week after the last dose.1
The safety and effectiveness of eflornithine have been established in pediatric patients with high-risk neuroblastoma who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy.1 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).1
The safety and effectiveness of eflornithine have not been established in pediatric patients for other indications.1
An increased exposure to eflornithine has been observed in patients with moderate (estimated glomerular filtration rate [eGFR] <60 mL/min) and severe (eGFR (<30 mL/min) renal impairment compared to patients with normal renal function.1 Patients with severe renal impairment should be administered a reduced eflornithine dose.1 Patients with moderate renal impairment should be monitored closely for increased adverse reactions including hepatotoxicity, myelosuppression, and hearing loss.1
The most common adverse effects of eflornithine (≥5% of patients) reported in clinical studies include hearing loss, otitis media, pyrexia, pneumonia, and diarrhea.1 The most common Grade 3 or 4 laboratory abnormalities (≥2% of patients) reported in clinical studies include increased ALT, increased AST, decreased neutrophil count, and decreased hemoglobin.1
Eflornithine has no clinically relevant drug interactions.5
Eflornithine does not induce or inhibit any cytochrome P-450 (CYP) enzymes or act as a substrate or inhibitor of major drug transporters.5
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 .1 Polyamines are involved in differentiation and proliferation of mammalian cells and are important for neoplastic transformation.1 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.1 In vitro, eflornithine induced senescence and suppressed neurosphere formation in MYCN -amplified and MYCN non-amplified neuroblastoma cells, indicating a cytostatic effect.1 Treatment with eflornithine prevented or delayed tumor formation in mice injected with limiting dilutions of MYCN -amplified neuroblastoma cells.1
Following oral administration of eflornithine, peak plasma concentrations (Cmax) were achieved 3.5 hours post dosing.1 The Cmax and AUC are not affected by food (high fat and high calories).1 Administration of crushed tablets in a standard pudding admixture did not alter eflornithine exposure.1 Eflornithine does not specifically bind to human plasma proteins.1 The terminal plasma elimination half-life of eflornithine is 3.5 hours.1 Eflornithine is not highly metabolized; 80% is excreted unchanged in the urine.5 Pharmacokinetic analyses suggests that age (range: 1 to 19 years), sex, or body surface area (range: 0.4 to 2 m2) and mild hepatic impairment (bilirubin ≤ the upper limit of normal [ULN] and AST > ULN or bilirubin <1 times ULN and any AST) had no clinically meaningful effects on eflornithine exposure.1 Exposure of eflornithine was 2- or 4-fold higher in adults with moderate or severe renal impairment, respectively, when compared to adults with normal renal function following administration of a single 576 mg dose.1
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].
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 is obtained through a designated specialty pharmacy. Contact manufacturer or consult the eflornithine website ([Web]) for specific availability information.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 192 mg (of eflornithine) | Iwilfin® | US WorldMeds |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions June 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. US WorldMeds. Iwilfin® (eflornithine hydrochloride) oral tablets prescribing information. Louisville, KY; 2024 Nov.
2. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2024 Sep 12. [Web]
3. Sholler GLS, Ferguson W, Bergendahl G et al. Maintenance DFMO increases survival in high risk neuroblastoma. Sci Rep . 2018; 8(1):14445.
4. Oesterheld J, Ferguson W, Kraveka JM et al. Eflornithine as postimmunotherapy maintenance in high-risk neuroblastoma: externally controlled, propensity score-matched survival outcome comparisons. J Clin Oncol . 2024; 42(1):90-102.
5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 215500Orig1s000: Multi-discipline review. From the FDA Website. Accessed 2024 Sep 12. [Web]