2.1 Recommended Testing Before Initiating IWILFIN

Prior to initiating IWILFIN, perform complete blood count, liver function tests, and baseline audiogram [see Warnings and Precautions (5.1-5.3)].

2.2 Recommended Dosage of IWILFIN

The recommended IWILFIN dosage, based on body surface area (BSA), is provided in Table 1.

Administer IWILFIN orally twice daily for two years or until recurrence of disease or unacceptable toxicity.

Recalculate the BSA dosage every 3 months during treatment with IWILFIN.

2.3 Dosage Recommendations for Renal Impairment

For the treatment of patients with severe renal impairment (eGFR <30 mL/min), reduce the recommended dose of IWILFIN by 50% as described in Table 2 [see Use in Specific Populations (8.5), Clinical Pharmacology (12.3)].

2.4 Dosage Modifications for Adverse Reactions

The recommended dose reductions for adverse reactions are provided in Table 3.

If subsequent adverse reactions occur, continue dose reduction until reaching the minimum dose of one 192 mg tablet once per day. Permanently discontinue IWILFIN if the patient is unable to tolerate the minimum dose of 192 mg once daily.

The recommended dosage modifications of IWILFIN for the management of adverse reactions are provided in Table 4.

2.5 Administration, Crushed Preparation, and Missed Dose Instructions

5.1 Myelosuppression

IWILFIN can cause myelosuppression. In the pooled safety population [see Adverse Reactions (6.1)], 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.

Monitor blood counts including neutrophil count, platelet count, and hemoglobin level prior to administration of IWILFIN and periodically during treatment. Withhold, reduce the dose, or permanently discontinue IWILFIN based on severity [see Dosage and Administration (2.4)].

5.2 Hepatotoxicity

IWILFIN can cause hepatotoxicity. In the pooled safety population [see Adverse Reactions (6.1)], 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. IWILFIN 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 IWILFIN, every month for the first six 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 IWILFIN based on severity [see Dosage and Administration (2.4) and Adverse Reactions (6.1)].

5.3 Hearing Loss

IWILFIN can cause hearing loss. In the pooled safety population [see Adverse Reactions (6.1)], 81% of patients had an abnormal audiogram at baseline. New or worsening hearing loss occurred in 13% of patients who received IWILFIN; 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. IWILFIN was discontinued due to hearing loss in 1.4% of patients. Among all patients with new or worsening hearing loss during IWILFIN 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 IWILFIN based on severity [see Dosage and Administration (2.1, 2.4)].

5.4 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, IWILFIN 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 IWILFIN and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with IWILFIN and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in clinical practice.

The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to IWILFIN as a single agent, taken orally at doses ranging from 192 - 768 mg twice daily, based on body surface area (BSA), until disease progression, unacceptable toxicity, or for a maximum of 2 years in patients who demonstrated at least a partial response to prior multiagent, multimodality therapy for newly diagnosed or relapsed/refractory high-risk neuroblastoma in Study 3b (n=101; NCT02395666) and Study 14 (n=259; NCT02679144). Among 360 patients who received IWILFIN, 84% were exposed for 6 months or longer and 73% were exposed for greater than one year. In this pooled safety population, the most common (≥5%) adverse reactions were hearing loss (11%), otitis media (10%), pyrexia (7%), pneumonia (5%), and diarrhea (5%). The most common (≥2%) Grade 3 or 4 laboratory abnormalities were increased ALT (11%), increased AST (6%), decreased neutrophils (4.2%), and decreased hemoglobin (3.3%).

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

Based on animal data and its mechanism of action, IWILFIN can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

The safety and effectiveness of IWILFIN 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 IWILFIN 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) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.1)].

The safety and effectiveness of IWILFIN have not been established in pediatric patients for other indications [see Indications and Usage (1)].

8.5 Renal Impairment

Patients with moderate (eGFR <60 mL/min) and severe (eGFR <30 mL/min) renal impairment have a higher exposure to eflornithine than patients with normal renal function which can increase the risk for toxicity [see Clinical Pharmacology (12.3)]. Reduce the dose in patients with severe renal impairment [see Dosage and Administration (2.3)]. Monitor patients with moderate renal impairment closely for increased adverse reactions including hepatotoxicity, myelosuppression, and hearing loss [see Dosage and Administration (2.4)].

12.1 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.

12.2 Pharmacodynamics

Eflornithine exposure-response relationships and the time course of pharmacodynamic responses are unknown.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year carcinogenicity study, once daily oral administration of eflornithine to female rats did not result in drug-related neoplasms at doses up to 600 mg/kg/day (10.5 times the human Cmax at the recommended clinical dose of 1152 ± 384 mg/m2).

Eflornithine was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay.

Dedicated fertility studies were not conducted with eflornithine.

Study 3b

Study 3b (NCT02395666) was a multi-center, open label, non-randomized trial with two cohorts. Eligible patients in one cohort (Stratum 1) were pediatric patients with high-risk neuroblastoma (HRNB) who demonstrated at least a partial response to prior multiagent, multimodality therapy, including induction, consolidation, and anti-GD2 immunotherapy. A total of 105 eligible patients received IWILFIN orally twice daily, dosage based on body surface area (BSA) until disease progression, unacceptable toxicity, or for a maximum of 2 years [see Dosage and Administration (2.1)]. Tumor assessments were performed at 3, 6, 9, 12, 18 months, completion of treatment, and as clinically indicated. Following completion of IWILFIN therapy, patients were followed for a total duration of 7 years. The major efficacy outcome measure was event free survival (EFS), defined as disease progression, relapse, secondary cancer, or death due to any cause. An additional efficacy outcome measure was overall survival (OS), defined as death due to any cause. Study 3b was prospectively designed to compare outcomes to the historical EFS rate from Study ANBL0032 reported in published literature.

External Comparator: ANBL0032

The external control arm was derived from 1,241 patients on the experimental arm of Study ANBL0032, a multi-center, open-label, randomized trial of dinutuximab, granulocyte-macrophage colony-stimulating factor, interleukin-2, and cis-retinoic acid compared to cis-retinoic acid alone in pediatric patients with HRNB previously treated with induction and consolidation therapy who achieved at least a partial response to prior autologous stem cell transplant. Tumor assessments were performed post-immunotherapy at 3, 6, 9, 12, 18, 24, 30, and 36 months, then per standard of care for a total of 10 years.

Externally Controlled Trial

The efficacy population for the comparative analysis of Study 3b and ANBL0032 included patients from both studies who were less than 21 years of age with histologic verification of HRNB 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, and did not experience an EFS event prior to starting IWILFIN maintenance therapy (for Study 3b), or for at least 30 days from the end of immunotherapy (for ANBL0032). Eligible patients on Study 3b received immunotherapy on ANBL0032 or were treated off study according to the ANBL0032 protocol. Patients who met the criteria for the comparison and had complete data for specified clinical covariates were matched (1:3) using propensity scores; the matched efficacy populations for the primary analysis included 90 patients treated with IWILFIN and 270 control patients from ANBL0032. The demographic characteristics of the primary analysis population (N=360) were 59% male; median age at diagnosis 3 years (range: 0.1 to 20.1); 88% White, 6% Black, 4% Asian, 7% Hispanic. The majority of patients had Stage 4 disease (86%) and MYCN amplification was observed in 44% of tumors. End of immunotherapy responses were complete response (CR; 87%), very good partial response (VGPR; 8%), or partial response (PR; 5%).

In the protocol-specified primary analysis, the EFS hazard ratio (HR) was 0.48 (95% CI: 0.27, 0.85) and OS HR was 0.32 (95% CI: 0.15, 0.70). The Kaplan-Meier plot for the primary analysis of EFS, with shaded bands for each curve representing the point-wise 95% confidence intervals, is shown in Figure 1. Given the uncertainty associated with the externally controlled study design, supplementary analyses in subpopulations or using alternative statistical methods were performed. In these analyses, the EFS HR ranged from 0.43 (95% CI: 0.23, 0.79) to 0.59 (95% CI: 0.28, 1.27), and the OS HR ranged from 0.29 (95% CI: 0.11, 0.72) to 0.45 (95% CI: 0.21, 0.98).

Figure 1: Kaplan-Meier Curve for Event Free Survival for Protocol-Specified Primary Analysis in the Externally Controlled Trial

Store at room temperature, 20°C to 25°C (68°F to77°F), excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Myelosuppression

Inform patients and caregivers of the risk of bone marrow suppression and to promptly report any signs or symptoms of thrombocytopenia, anemia, or infection [see Warnings and Precautions (5.1)].

Hepatotoxicity

Inform patients and caregivers of the risk of hepatotoxicity and to promptly report any signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.2)].

Hearing Loss

Inform patients and caregivers of the risk of hearing loss, and to promptly report any signs or symptoms of new or worsening hearing loss [see Warnings and Precautions (5.3)].

Embryofetal Toxicity

Inform patients and caregivers that IWILFIN can be harmful to a developing fetus and cause loss of pregnancy [see Warnings and Precautions (5.4)]. Advise females of reproductive potential to use effective contraception during treatment with IWILFIN and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with IWILFIN and for 1 week after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with IWILFIN and for 1 week after the last dose [see Use in Specific Populations (8.2)].