Version May 2024
Neuroblastoma, high-risk: Note: For use in patients who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy.
Children ≥1 year and Adolescents: Iwilfin: Note: Recalculate BSA every 3 months and adjust dose accordingly.
0.25 to <0.5 m2: Oral: 192 mg twice daily.
0.5 to <0.75 m2: Oral: 384 mg twice daily.
0.75 to ≤1.5 m2: Oral: 576 mg twice daily.
>1.5 m2: Oral: 768 mg twice daily.
Trypanosoma brucei gambiense infection (sleeping sickness ); second-stage infection: Limited data available (Ref): Note: Parenteral product only available through special distribution programs; refer to Prescribing Access for additional information.
NECT regimen: Children and Adolescents: IV: 200 mg/kg/dose every 12 hours for 7 days in combination with nifurtimox. NECT is the preferred regimen over monotherapy; it has been found to be safer, easier to administer and complete the course, and less expensive than eflornithine monotherapy (Ref).
Monotherapy (difluoromethylornithine [DFMO]):
Children <12 years: IV: 150 mg/kg/dose every 6 hours for 14 days.
Children ≥12 years and Adolescents: IV: 100 mg/kg/dose every 6 hours for 14 days.
Dosage adjustment for toxicity:
Neuroblastoma; high-risk: Children ≥1 year and Adolescents: Iwilfin: Oral: If an adverse reaction occurs, dose should be reduced based on current dose. If subsequent adverse reaction occurs, continue dose reductions until reaching the minimum dose; if patient is unable to tolerate the minimum dose then permanently discontinue therapy.
|
Current oral daily dose |
Reduced oral dose for toxicity management |
|---|---|
|
768 mg twice daily |
576 mg twice daily |
|
576 mg twice daily |
384 mg twice daily |
|
384 mg twice daily |
192 mg twice daily |
|
192 mg twice daily |
192 mg once daily |
|
192 mg once daily |
Permanently discontinue therapy if patient unable to tolerate dose. |
|
Adverse reaction |
Severity |
Eflornithine dosage modification |
|---|---|---|
|
Hematologic toxicity | ||
|
Anemia |
Hemoglobin <8 g/dL (first occurrence) |
Withhold eflornithine until hemoglobin ≥8 g/dL; resume eflornithine at the same dose. |
|
Hemoglobin <8 g/dL (recurrent) |
Withhold eflornithine until hemoglobin ≥8 g/dL; resume eflornithine at the next reduced dose level. | |
|
Neutropenia |
ANC <500/mm3 |
Withhold eflornithine until ANC ≥500/mm3. Recovery within 7 days of interruption: Resume eflornithine at the same dose. Recovery after 7 days of interruption: Resume eflornithine at the next reduced dose level. |
|
Thrombocytopenia |
Platelets <25,000/mm3 |
Withhold eflornithine until platelets ≥25,000/mm3. Recovery within 7 days of interruption: Resume eflornithine at the same dose. Recovery within 7 to 14 days of interruption: Resume eflornithine at the next reduced dose level. Not recovered within 14 days of interruption: Permanently discontinue eflornithine. |
|
Nonhematologic toxicity | ||
|
GI toxicity (eg, nausea, vomiting, diarrhea) |
Grade 3 |
If symptoms respond to supportive treatment (eg, anti-emetic or anti-diarrheal therapy), continue eflornithine at the same dose. If symptoms do not respond to supportive treatment, withhold eflornithine until recovery to ≤ grade 2; resume eflornithine at the next reduced dose level. |
|
Ototoxicity |
Clinically concerning new or worsening hearing loss compared to baseline audiogram |
Continue eflornithine dosing and repeat audiogram in 3 weeks. Improvement on repeat audiogram: Continue eflornithine at the same dose. Persistent clinically concerning changes on repeat audiogram: Withhold eflornithine for up to 30 days and repeat audiogram. If stable or improved, resume eflornithine at the next reduced dose level. May also require hearing aids and/or eflornithine discontinuation based on severity. |
|
Other adverse reactions |
Grade 3 or 4 |
Withhold eflornithine until recovery to ≤ grade 2; resume eflornithine at the next reduced dose level. |
|
Grade 4 (recurrent) |
Permanently discontinue eflornithine. | |
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Children ≥1 year and Adolescents:
Neuroblastoma: Oral: Iwilfin: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Trypanosoma brucei gambiense infection (sleeping sickness): IV: Dose should be adjusted although no specific guidelines are available.
Neuroblastoma: Oral: Iwilfin:
Children ≥1 year and Adolescents:
Baseline hepatic impairment:
Mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin >1 times ULN and any AST): Oral: There are no dosage adjustments provided in the manufacturer's labeling; however, no clinically significant differences in eflornithine pharmacokinetics were noted based on mild hepatic impairment.
Moderate to severe hepatic impairment: Oral: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Acute hepatotoxicity during treatment:
AST or ALT ≥10 times ULN: Oral: Withhold eflornithine until recovery to <10 times ULN. If recovery occurs within 7 days of interruption, resume at the same dose. If recovery occurs after 7 days of interruption, resume at the next reduced dose level.
|
Current oral daily dose |
Reduced oral dose for toxicity management |
|---|---|
|
768 mg twice daily |
576 mg twice daily |
|
576 mg twice daily |
384 mg twice daily |
|
384 mg twice daily |
192 mg twice daily |
|
192 mg twice daily |
192 mg once daily |
|
192 mg once daily |
Permanently discontinue therapy if patient unable to tolerate dose. |
(For additional information see "Eflornithine (United States: Availability of intravenous preparation limited to CDC and WHO distribution programs) (systemic): Drug information")
Neuroblastoma, high-risk (Iwilfin only): Note: Recalculate the BSA dose every 3 months during treatment.
Oral:
|
BSA |
Eflornithine oral dosage |
|---|---|
|
>1.5 m2 |
768 mg twice daily; continue until disease recurrence, unacceptable toxicity, or a maximum of 2 years. |
|
0.75 m2 to 1.5 m2 |
576 mg twice daily; continue until disease recurrence, unacceptable toxicity, or a maximum of 2 years. |
Missed doses: Oral: Administer the missed dose as soon as possible; if the next dose is due within 7 hours, the missed dose should be skipped. If vomiting occurs following administration, do not administer an additional dose; continue dosing with next scheduled dose.
West African trypanosomiasis, second-stage disease (off-label use) (Ornidyl only):
Note: For use in patients with second-stage infection with CNS involvement caused by Trypanosoma brucei gambiense (West African).
Combination therapy: IV: 200 mg/kg every 12 hours for 7 days in combination with nifurtimox (Ref).
Monotherapy (alternative therapy): IV: 100 mg/kg every 6 hours for 14 days (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Oral: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
IV (off label): No specific recommendations are available.
Hepatic impairment prior to treatment initiation:
Mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin >1 times ULN and any AST): Oral: There are no dosage adjustments provided in the manufacturer's labeling; however, no clinically significant differences in eflornithine pharmacokinetics were noted based on mild hepatic impairment.
Moderate to severe hepatic impairment: Oral: There are no dosage adjustments provided in the manufacturer's labeling.
IV (off label): No specific recommendations are available.
Acute hepatotoxicity during treatment:
AST or ALT ≥10 times ULN: Oral: Withhold eflornithine until recovery to <10 times ULN. If recovery occurs within 7 days of interruption, resume at the same dose. If recovery occurs after 7 days of interruption, resume at the next reduced dose level.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported for the oral formulation in children and adolescents.
>10%:
Gastrointestinal: Diarrhea (15%; grade 3: 4%), vomiting (11%; grade 3: 1%)
Ophthalmic: Conjunctivitis (11%)
Otic: Otitis media (32%)
Respiratory: Allergic rhinitis (11%), cough (15%), pneumonia (12%), sinusitis (13%), upper respiratory tract infection (11%)
Miscellaneous: Fever (11%)
1% to 10%:
Dermatologic: Alopecia (<5%), skin infection (7%), skin rash (<5%)
Endocrine & metabolic: Decreased serum glucose (2%), decreased serum potassium (2%), decreased serum sodium (2%), increased serum glucose (1%), increased serum potassium (1%)
Genitourinary: Urinary tract infection (6%)
Hematologic & oncologic: Decreased hemoglobin (5%; grade 3: 2%), decreased neutrophils (9%; grades 3/4: 8%), decreased platelet count (1%), decreased white blood cell count (2%)
Hepatic: Increased serum alanine aminotransferase (9%), increased serum alkaline phosphatase (5%), increased serum aspartate aminotransferase (8%)
Neuromuscular & skeletal: Limb pain (<5%)
Otic: Hearing loss (7%)
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Hepatotoxicity: Grades 3 or 4 elevations of AST, ALT, and bilirubin have been observed in patients treated with eflornithine, leading to dosage modification or discontinuation in a small percentage of patients.
• Myelosuppression: Eflornithine may cause myelosuppression, including grade 3 anemia, grades 3 or 4 neutropenia, and grades 3 or 4 thrombocytopenia. Febrile neutropenia and bone marrow failure occurred rarely.
• Ototoxicity: Eflornithine may cause hearing loss. In the clinical study, more than three-quarters of treated patients had an abnormal audiogram at baseline, with new or worsening hearing loss occurring in 12% of patients (including worsening to grades 3 or 4 hearing loss and tinnitus in one patient). New or worsening hearing loss during treatment with eflornithine led to new hearing aid use, dosage modifications, and dosage discontinuation in some patients. Among all patients that experienced hearing loss with eflornithine, ~10% resolved to baseline, and of those who had dosage modification, approximately two-thirds of patients improved or had resolution to baseline.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrochloride:
Iwilfin: 192 mg [contains corn starch]
No
Tablets (Iwilfin Oral)
192 mg (per each): $108.00
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Eflornithine IV (off label): Injectable eflornithine is donated to the World Health Organization (WHO) by the manufacturer. In the United States, eflornithine injection is available through the CDC for treatment of second-stage African trypanosomiasis (caused by Trypanosoma brucei gambiense) with CNS involvement. Further information may be found on the WHO website at https://www.who.int/health-topics/human-african-trypanosomiasis or by contacting the CDC Drug Service (404-639-3670). Additional information from the CDC is available at https://www.cdc.gov/laboratory/drugservice/formulary.html.
Oral: Administer with or without food; tablets may be swallowed whole, chewed, or crushed. If dose is vomited, an additional dose should not be administered; continue with next scheduled dose.
Crushed tablets preparation: For patients with difficulty swallowing tablets, eflornithine may be chewed, or crushed and mixed with 2 tablespoons of soft food or liquid. Visually confirm the entire contents of the dose are administered; if crushed tablet particles remain, may mix with an additional small volume (eg, no more than 1 ounce [30 mL]) of soft food or liquid. Discard crushed preparation if not administered within 1 hour.
Parenteral: IV: Administer diluted solution by IV infusion over 120 minutes; not for IM administration (Ref).
Oral: Administer with or without food; tablets may be swallowed whole, chewed, or crushed.
Crushed tablets preparation: For patients with difficulty swallowing tablets, eflornithine may be chewed, or crushed and mixed with 2 tablespoons of soft food or liquid. Visually confirm the entire contents of the dose are administered; if crushed tablet particles remain, may mix with an additional small volume (eg, no more than 1 ounce [30 mL]) of soft food or liquid. Discard crushed preparation if not administered within 1 hour.
IV (off label): Administer IV only; do not administer IM. Dilute prior to use and infuse over 120 minutes; replace IV catheter at least every 48 hours (Ref).
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Eflornithine may cause developmental toxicity.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (Ref).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (Ref). Refer to institution-specific handling policies/procedures.
Oral: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Discard crushed preparation if not administered within 1 hour.
IV (off label): Use within 24 hours of preparation.
Oral: Reduction in risk of relapse of high-risk neuroblastoma in patients who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy (FDA approved in ages ≥1 year and adults).
Parenteral: Treatment of meningoencephalitic stage of Trypanosoma brucei gambiense infection (sleeping sickness) (available through World Health Organization [WHO]).
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its lists of drug classes which have a heightened risk of causing significant patient harm when used in error.
None known.
There are no known significant interactions.
Verify pregnancy status prior to initiating treatment in patients who could become pregnant.
Patients who may become pregnant should use effective contraception during therapy and for 1 week after the last dose of eflornithine. Patients with partners who could become pregnant should also use effective contraception during therapy and for 1 week after the last eflornithine dose.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to eflornithine may cause fetal harm. Embryolethality was observed following oral administration to pregnant rats and rabbits during the period of organogenesis with doses equivalent to the recommended human dose (based on BSA).
Limited outcome data related to systemic eflornithine in pregnancy are available following use as part of combination therapy for the treatment of West African trypanosomiasis (Ref).
Neuroblastoma: Monitor CBC (prior to therapy and periodically during treatment); liver function tests (ALT, AST, and total bilirubin) (prior to therapy, every month for the first 6 months of treatment, then every 3 months or as clinically indicated; monitor more frequently in patients with transaminase or bilirubin elevations). Obtain baseline audiogram; repeat audiogram at 6-month intervals or as clinically indicated to monitor hearing loss. Verify pregnancy status prior to initiating treatment in patients who could become pregnant.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (Ref) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Trypanosoma brucei gambiense infection (IV administration): CBC with platelet counts. Monitor for signs/symptoms of hearing loss.
Eflornithine exerts antitumor and antiprotozoal effects through specific, irreversible inhibition of the enzyme ornithine decarboxylase (ODC). ODC is the rate-limiting enzyme in the biosynthesis of polyamines in nucleated cells. Polyamines are necessary for the synthesis of DNA, RNA, and proteins and are, therefore, necessary for cell growth and differentiation. Mammalian cells depend on ornithine decarboxylase to produce polyamines.
In the treatment of neuroblastoma, ODC inhibition by eflornithine additionally reverses the effects of the LIN28/Let7 metabolic pathway (involved in cancer stem cell regulation and glycolytic metabolism), decreasing expression of oncogenic drivers MYCN and LIN28B (Ref). In vitro, eflornithine suppressed neurosphere formation in neuroblastoma cell lines, regardless of MYCN amplification (Ref).
Distribution: Oral: Vd: 24.3 L.
Half-life elimination: Oral: 3.5 hours; IV (off label): 1.5 to 5 hours (Ref).
Time to peak: Oral: 3.5 hours.
Excretion: Clearance: Oral: 5.3 L/hour.
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