ADVERSE REACTIONS SECTION.

6ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Myelosuppression [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)] Hearing Loss [see Warnings and Precautions (5.3)] Myelosuppression [see Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)] Hearing Loss [see Warnings and Precautions (5.3)] Most common adverse reactions (incidence >=5%) are hearing loss, otitis media, pyrexia, pneumonia, and diarrhea. (6.1)Most common Grade or laboratory abnormalities (incidence >=2%) are increased ALT, increased AST, decreased neutrophil count, and decreased hemoglobin. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact US WorldMeds at 1-877-IWILFIN or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Most common adverse reactions (incidence >=5%) are hearing loss, otitis media, pyrexia, pneumonia, and diarrhea. (6.1). Most common Grade or laboratory abnormalities (incidence >=2%) are increased ALT, increased AST, decreased neutrophil count, and decreased hemoglobin. (6.1). 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 maximum of years in patients who demonstrated at least 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 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 or laboratory abnormalities were increased ALT (11%), increased AST (6%), decreased neutrophils (4.2%), and decreased hemoglobin (3.3%).. Study 3bThe safety of IWILFIN was evaluated in Study 3b [see Clinical Studies (14.1)]. Eligible patients were pediatric patients with high-risk neuroblastoma (HRNB) who demonstrated at least partial response to prior multiagent, multimodality therapy including induction, consolidation, and anti-GD2 immunotherapy. Patients received IWILFIN as 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 maximum of years (N=85). Among patients who received IWILFIN, 93% were exposed for months or longer and 89% were exposed for greater than one year.The median age of patients who received IWILFIN was years (range: to 17); 59% male; 85% White, 7% Black, 1% Asian, 8% Hispanic or Latino; 87% had International Neuroblastoma Staging System Stage disease; 47% had neuroblastoma with known MYCN-amplification.Serious adverse reactions occurred in 12% of patients who received IWILFIN. Serious adverse reactions in >1 patient included skin infection (3 patients).Permanent discontinuation of IWILFIN due to an adverse reaction occurred in 11% of patients. Adverse reactions which resulted in permanent discontinuation of IWILFIN in >1 patient included hearing loss.Dose reductions of IWILFIN due to an adverse reaction occurred in 8% of patients. Adverse reactions which required dose reductions in >1 patient included hearing loss.The most common (>=5%) adverse reactions, including laboratory abnormalities, were otitis media, diarrhea, cough, sinusitis, pneumonia, upper respiratory tract infection, conjunctivitis, vomiting, pyrexia, allergic rhinitis, decreased neutrophils, increased ALT, increased AST, hearing loss, skin infection, and urinary tract infection.Table summarizes the adverse reactions in Study 3b.Table 5: Adverse Reactions (>=5%) in Patients with HRNB Who Received IWILFIN in Study 3bAdverse ReactionSeverity as defined by CTCAE Version 4.03. IWILFIN(n=85)All GradesGrade adverse events were not comprehensively collected in Study 3b. No Grade or events were reported. (%)Grade 3(%)InfectionsOtitis media322.4Sinusitis130Pneumonia121.2Upper respiratory tract infection110Conjunctivitis 110Skin infection74.7Urinary tract infection61.2Gastrointestinal DisordersDiarrheaIncludes colitis. 153.5Vomiting111.2Respiratory DisordersCough150Allergic rhinitis110General DisordersPyrexia111.2Ear and Labyrinth DisordersHearing loss77Clinically relevant adverse reactions in <5% of patients who received IWILFIN included rash, extremity pain, and alopecia.Table summarizes the laboratory abnormalities in Study 3b.Table 6:Select Laboratory Abnormalities (>=1%) in Patients with HRNB Who Received IWILFIN in Study 3bLaboratory AbnormalitySeverity as defined by CTCAE Version 4.03. IWILFIN(n=85)All GradesGrade adverse events were not comprehensively collected in Study 3b. No Grade events occurred. (%)Grade or 4(%)ChemistryIncreased ALT97No Grade events occurred. Increased AST86 Increased alkaline phosphatase4.72.4 Decreased potassium2.42.4 Decreased glucose2.41.1Decreased sodium2.42.4 Increased potassium1.20Increased glucose1.20HematologyDecreased neutrophils98Decreased hemoglobin4.72.4 Decreased white blood cells2.40Decreased platelets1.20.

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY. 12.1Mechanism 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 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 cytostatic effect. Treatment with eflornithine prevented or delayed tumor formation in mice injected with limiting dilutions of MYCN-amplified neuroblastoma cells.. 12.2Pharmacodynamics. Eflornithine exposure-response relationships and the time course of pharmacodynamic responses are unknown.. Cardiac ElectrophysiologyAt the recommended dose, IWILFIN did not result in large mean increase (i.e., >20 ms) of the QTc interval.. 12.3Pharmacokinetics. AbsorptionFollowing oral administrations of IWILFIN, peak plasma concentrations of eflornithine (Cmax) were achieved (Tmax) 3.5 hours post dosing. Effect of FoodThe Cmax and AUC (area under the concentration-time curve) of eflornithine were not affected by food (high fat and high calories). Administration of crushed tablets in standard pudding admixture had no effect on eflornithine exposure (Cmax and AUC6h). DistributionEflornithine does not specifically bind to human plasma proteins. Eflornithine volume of distribution (Vz/F) is 24.3 L.. Elimination. ExcretionTerminal plasma elimination half-life of eflornithine is 3.5 hours. Clearance (CL/F) is 5.3 L/h. Specific PopulationsPharmacokinetic analyses from patients in Study 14 suggested that age (1 year to 19 years), sex, or body surface area (0.4 m2 to m2), and mild hepatic impairment (bilirubin <=ULN and AST>ULN or bilirubin >1 ULN and any AST) had no clinically meaningful effects on eflornithine exposure.. Renal ImpairmentFollowing oral administration of single IWILFIN dose of 576 mg, exposure (AUC) of eflornithine was 2-fold higher in adults with moderate renal impairment and 4-fold higher in adults with severe renal impairment when compared to adults with normal renal function.

CLINICAL STUDIES SECTION.

14CLINICAL STUDIES. The efficacy of IWILFIN is based on an externally controlled trial comparison of Study 3b (investigational arm) and Study ANBL0032 (clinical trial-derived external control arm).. Study 3bStudy 3b (NCT02395666) was 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 partial response to prior multiagent, multimodality therapy, including induction, consolidation, and anti-GD2 immunotherapy. total of 105 eligible patients received IWILFIN orally twice daily, dosage based on body surface area (BSA) until disease progression, unacceptable toxicity, or for maximum of 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 total duration of 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: ANBL0032The external control arm was derived from 1,241 patients on the experimental arm of Study ANBL0032, 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 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 total of 10 years. Externally Controlled TrialThe 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 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 years (range: 0.1 to 20.1); 88% White, 6% Black, 4% Asian, 7% Hispanic. The majority of patients had Stage 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. Figure 1.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 maximum of years in patients who demonstrated at least 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 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 or laboratory abnormalities were increased ALT (11%), increased AST (6%), decreased neutrophils (4.2%), and decreased hemoglobin (3.3%).. Study 3bThe safety of IWILFIN was evaluated in Study 3b [see Clinical Studies (14.1)]. Eligible patients were pediatric patients with high-risk neuroblastoma (HRNB) who demonstrated at least partial response to prior multiagent, multimodality therapy including induction, consolidation, and anti-GD2 immunotherapy. Patients received IWILFIN as 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 maximum of years (N=85). Among patients who received IWILFIN, 93% were exposed for months or longer and 89% were exposed for greater than one year.The median age of patients who received IWILFIN was years (range: to 17); 59% male; 85% White, 7% Black, 1% Asian, 8% Hispanic or Latino; 87% had International Neuroblastoma Staging System Stage disease; 47% had neuroblastoma with known MYCN-amplification.Serious adverse reactions occurred in 12% of patients who received IWILFIN. Serious adverse reactions in >1 patient included skin infection (3 patients).Permanent discontinuation of IWILFIN due to an adverse reaction occurred in 11% of patients. Adverse reactions which resulted in permanent discontinuation of IWILFIN in >1 patient included hearing loss.Dose reductions of IWILFIN due to an adverse reaction occurred in 8% of patients. Adverse reactions which required dose reductions in >1 patient included hearing loss.The most common (>=5%) adverse reactions, including laboratory abnormalities, were otitis media, diarrhea, cough, sinusitis, pneumonia, upper respiratory tract infection, conjunctivitis, vomiting, pyrexia, allergic rhinitis, decreased neutrophils, increased ALT, increased AST, hearing loss, skin infection, and urinary tract infection.Table summarizes the adverse reactions in Study 3b.Table 5: Adverse Reactions (>=5%) in Patients with HRNB Who Received IWILFIN in Study 3bAdverse ReactionSeverity as defined by CTCAE Version 4.03. IWILFIN(n=85)All GradesGrade adverse events were not comprehensively collected in Study 3b. No Grade or events were reported. (%)Grade 3(%)InfectionsOtitis media322.4Sinusitis130Pneumonia121.2Upper respiratory tract infection110Conjunctivitis 110Skin infection74.7Urinary tract infection61.2Gastrointestinal DisordersDiarrheaIncludes colitis. 153.5Vomiting111.2Respiratory DisordersCough150Allergic rhinitis110General DisordersPyrexia111.2Ear and Labyrinth DisordersHearing loss77Clinically relevant adverse reactions in <5% of patients who received IWILFIN included rash, extremity pain, and alopecia.Table summarizes the laboratory abnormalities in Study 3b.Table 6:Select Laboratory Abnormalities (>=1%) in Patients with HRNB Who Received IWILFIN in Study 3bLaboratory AbnormalitySeverity as defined by CTCAE Version 4.03. IWILFIN(n=85)All GradesGrade adverse events were not comprehensively collected in Study 3b. No Grade events occurred. (%)Grade or 4(%)ChemistryIncreased ALT97No Grade events occurred. Increased AST86 Increased alkaline phosphatase4.72.4 Decreased potassium2.42.4 Decreased glucose2.41.1Decreased sodium2.42.4 Increased potassium1.20Increased glucose1.20HematologyDecreased neutrophils98Decreased hemoglobin4.72.4 Decreased white blood cells2.40Decreased platelets1.20.

DOSAGE & ADMINISTRATION SECTION.

2DOSAGE AND ADMINISTRATION. Prior to initiation of IWILFIN, perform baseline audiogram, complete blood count, and liver function tests. (2.1, 5.3)Recommended dosage of IWILFIN is based on body surface area (see Table 1). (2.2)IWILFIN is taken orally twice daily with or without food until disease progression, unacceptable toxicity, or for maximum of two years. (2.2)IWILFIN tablets may be swallowed whole, chewed, or crushed and mixed with soft food or liquid. (2.5). Prior to initiation of IWILFIN, perform baseline audiogram, complete blood count, and liver function tests. (2.1, 5.3). Recommended dosage of IWILFIN is based on body surface area (see Table 1). (2.2). IWILFIN is taken orally twice daily with or without food until disease progression, unacceptable toxicity, or for maximum of two years. (2.2). IWILFIN tablets may be swallowed whole, chewed, or crushed and mixed with soft food or liquid. (2.5). 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 months during treatment with IWILFIN.Table 1: Recommended DoseBody Surface Area (m2)Dosage>1.5768 mg (four tablets) orally twice day0.75 to 1.5576 mg (three tablets) orally twice day 0.5 to 0.75384 mg (two tablets) orally twice day 0.25 to 0.5192 mg (one tablet) orally twice day 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 [see Use in Specific Populations (8.5), Clinical Pharmacology (12.3) ].Table 2: IWILFIN Dose Recommendations for Severely Renally Impaired Patients Body Surface Area (m2)Recommended Dosage for Patients with Severe Renal Impairment (eGFR <30 mL/min)>1.5384 mg (two tablets) orally twice day0.75 to 1.5384 mg (two tablets) in the morning and 192 mg (one tablet) in the evening0.5 to 0.75192 mg (one tablet) orally twice day0.25 to 0.5192 mg (one tablet) once day. 2.4 Dosage Modifications for Adverse Reactions. The recommended dose reductions for adverse reactions are provided in Table 3. Table 3: Recommended IWILFIN Dose Reductions for Toxicity ManagementCurrent DoseReduced Dose768 mg (four tablets) orally twice day576 mg (three tablets) orally twice day576 mg (three tablets) orally twice day384 mg (two tablets) orally twice day384 mg (two tablets) orally twice day192 mg (one tablet) orally twice day192 mg (one tablet) orally twice day192 mg (one tablet) orally once dailyIf 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. Table 4:Recommended IWILFIN Dosage Modifications for Adverse ReactionsAdverse ReactionSeveritySeverity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 Dosage ModificationMyelosuppression [see Warnings and Precautions (5.1)] Neutrophil count decreased<500/mm3 Withhold IWILFIN until recovery to >=500/mm3.If recovered within days, resume IWILFIN at the same dose.If recovered after days, resume IWILFIN at the next reduced dose level. Platelet count decreased<25,000/mm3 Withhold IWILFIN until recovery to >=25,000/mm3.If recovered within days, resume IWILFIN at the same dose.If recovered between and 14 days, resume IWILFIN at the next reduced dose level.If not recovered within 14 days, permanently discontinue IWILFIN.Anemia<8g/dLWithhold IWILFIN until recovery to >=8g/dL.Resume IWILFIN at the same dose.If anemia recurs (<8g/dL)Withhold IWILFIN until recovery to >=8g/dL.Resume IWILFIN at the next reduced dose level. Hepatotoxicity [see Warnings and Precautions (5.2)] Aspartate aminotransferase increasedorAlanine aminotransferase increasedAST or ALT >=10 ULN Withhold IWILFIN until recovery to <10 ULN.If recovered within days, resume IWILFIN at the same dose.If recovered after days, resume IWILFIN at the next reduced dose level. Hearing Loss [see Warnings and Precautions (5.3)]Hearing lossClinically concerning new or worsening hearing loss compared to IWILFIN baseline audiogramContinue dosing with IWILFIN and repeat audiogram in weeks.If improved, continue IWILFIN at the same dose.If clinically concerning changes persist, hold IWILFIN for up to 30 days and repeat audiogram.If stable or improved, resume IWILFIN at the next reduced dose level.Other Adverse Reactions [see Adverse Reactions (6.1)] Nausea, vomiting, or diarrheaGrade 3If symptoms respond to supportive treatment (e.g., anti-emetic, anti-diarrheal), continue dosing with IWILFIN at the same dose.If symptoms do not respond to treatment,Withhold IWILFIN until recovery to <= Grade 2.Resume IWILFIN at the next reduced dose level. Other adverse reactionsGrade or 4Withhold IWILFIN until recovery to <= Grade 2.Resume IWILFIN at the next reduced dose level. Recurrent Grade 4Permanently discontinue IWILFIN.. If recovered within days, resume IWILFIN at the same dose.. If recovered after days, resume IWILFIN at the next reduced dose level.. If recovered within days, resume IWILFIN at the same dose.. If recovered between and 14 days, resume IWILFIN at the next reduced dose level.. Resume IWILFIN at the same dose.. Withhold IWILFIN until recovery to >=8g/dL.. Resume IWILFIN at the next reduced dose level.. If recovered within days, resume IWILFIN at the same dose.. If recovered after days, resume IWILFIN at the next reduced dose level.. If improved, continue IWILFIN at the same dose.. If clinically concerning changes persist, hold IWILFIN for up to 30 days and repeat audiogram.. Withhold IWILFIN until recovery to <= Grade 2.. Resume IWILFIN at the next reduced dose level.. Resume IWILFIN at the next reduced dose level.. 2.5 Administration, Crushed Preparation, and Missed Dose Instructions. AdministrationAdminister IWILFIN orally twice daily, with or without food, for two years or until recurrence of disease or unacceptable toxicity [see Clinical Pharmacology (12.3)].IWILFIN tablets can be swallowed whole, chewed, or crushed.. Administer IWILFIN orally twice daily, with or without food, for two years or until recurrence of disease or unacceptable toxicity [see Clinical Pharmacology (12.3)].. IWILFIN tablets can be swallowed whole, chewed, or crushed.. Crushed PreparationFor patients who have difficulty swallowing tablets, IWILFIN can be chewed, or crushed then mixed with two tablespoons of soft food or liquid.Visually confirm the entire contents are consumed. If any crushed tablet particles remain in the container, mix with an additional small volume (e.g., no more than one ounce, 30 mL) of soft food or liquid.Discard crushed tablet preparation after one hour.. For patients who have difficulty swallowing tablets, IWILFIN can be chewed, or crushed then mixed with two tablespoons of soft food or liquid.. Visually confirm the entire contents are consumed. If any crushed tablet particles remain in the container, mix with an additional small volume (e.g., no more than one ounce, 30 mL) of soft food or liquid.. Discard crushed tablet preparation after one hour.. Missed DoseA missed dose of IWILFIN should be administered as soon as possible. If the next dose is due within hours, the missed dose should be skipped.If vomiting occurs after taking IWILFIN, an additional dose should not be administered. Continue with the next scheduled dose.. missed dose of IWILFIN should be administered as soon as possible. If the next dose is due within hours, the missed dose should be skipped.. If vomiting occurs after taking IWILFIN, an additional dose should not be administered. Continue with the next scheduled dose.

PREGNANCY SECTION.

8.1Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ], IWILFIN can cause fetal harm when administered to 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 [see Data]. There are no available data on the use of IWILFIN in pregnant women. Advise pregnant women and females of reproductive potential of the potential risk to 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.. Data. Animal DataIn 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 to 7) resulted in reduced fetal body weights and an increase in the incidence of skeletal variations (presence of 14th rudimentary rib, 14th full rib, 27th presacral vertebrae) at 200 mg/kg/day [approximately 0.8 to times the recommended human dose of 1152 +- 384 mg/m2/day based on body surface area (BSA)]. In 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 to 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 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 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 to 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 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 to 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.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug AdministrationIssued: 12/2023Patient InformationIWILFIN(R) (I-WILL-fin) (eflornithine) tabletsWhat is IWILFINIWILFIN is prescription medicine used to reduce the risk of relapse in adults and children with high-risk neuroblastoma (HRNB) who have had at least partial response to certain prior therapies.Before you take IWILFIN, tell your healthcare provider about all of your medical conditions, including if you:have hearing problemsare pregnant or plan to become pregnant. IWILFIN can harm your unborn baby. Tell your healthcare provider right away if you become pregnant during treatment with IWILFIN or think you may be pregnant.Females who are able to become pregnant should have pregnancy test before starting treatment with IWILFIN.You should use effective birth control during treatment with IWILFIN and for week after the last dose.Males who have female partners who are able to become pregnant should use effective birth control during treatment with IWILFIN and for week after the last dose. are breastfeeding or plan to breastfeed. It is not known if IWILFIN passes into your breast milk. Do not breastfeed during treatment with IWILFIN and for week after the last dose.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should take IWILFINTake IWILFIN exactly as your healthcare provider tells you to take it.Take IWILFIN times day with or without food.Swallow tablets whole. If you cannot swallow tablets whole, IWILFIN can be chewed, or crushed then mixed with soft food or liquid. If you are crushing IWILFIN tablets:IWILFIN can be crushed then mixed with tablespoons of soft food or liquid.Eat the entire mixture.If any crushed tablet pieces remain, mix with another small amount (about tablespoons) of soft food or liquid.Take all of the mixture within hour of mixing. Throw away any mixture left after hour. If you miss dose of IWILFIN, take it as soon as you remember. If it is within hours of your next scheduled dose, skip the missed dose and take your next dose at your regular time.If you vomit after taking dose, do not take an extra dose. Take your next dose at your regular time.What are the possible side effects of IWILFINIWILFIN may cause serious side effects, including:Low blood cell counts. IWILFIN can cause low blood cell counts and failure of your bone marrow to make enough platelets, red blood cells, or white blood cells. Your healthcare provider will monitor your blood cell counts before starting and during treatment with IWILFIN. Tell your healthcare provider right away if you develop symptoms of low blood cell counts, including:fever (temperature 100.4F or higher)easy bruising or bleedingblood in your urine or stoolsfeeling unusually tired or weakshortness of breathchills or shiveringLiver problems. Your healthcare provider will do blood tests before starting, every month for the first months, and regularly during treatment with IWILFIN to check your liver. Tell your healthcare provider if you develop symptoms of liver problems, including:your skin or the white part of your eyes turns yellow (jaundice)dark or tea-colored urinelight-colored stools (bowel movements)nausea or vomitingeasy bruising or bleedingloss of appetitepain, aching, or tenderness on the right side of your stomach-area (abdomen)New or worsening hearing loss. Hearing loss is common during treatment with IWILFIN and can also be serious. Your healthcare provider will check your hearing before you start and during treatment with IWILFIN. Some people have needed to use hearing aids. Tell your healthcare provider right way if you get ringing in your ears or any new or worsening hearing loss.The most common side effects of IWILFIN include:ear infectiondiarrheacoughsinus infectionpneumoniaupper respiratory tract infectionred and swollen eyes (pink eye)vomitingstuffy, runny, itchy nose or sneezing (allergic rhinitis)feverskin infectionurinary tract infectionThese are not all the possible side effects of IWILFIN.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store IWILFINStore IWILFIN at room temperature between 68F to 77F (20C to 25C).Keep IWILFIN and all medicines out of the reach of children.General information about the safe and effective use of IWILFIN:Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use IWILFIN for condition for which it was not prescribed. Do not give IWILFIN to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about IWILFIN that is written for health professionals.What are the ingredients in IWILFINActive ingredient: eflornithine Inactive ingredients: silicified microcrystalline cellulose, partially pregelatinized maize starch, colloidal silicon dioxide, and vegetable source magnesium stearate.Distributed by:USWM, LLC 4441 Springdale Road Louisville, KY 40241(C)2025. IWILFIN(R) is registered trademark of USWM, LLC.For more information, go to www.IWILFIN.com or call 1-877-IWILFIN.. have hearing problems. are pregnant or plan to become pregnant. IWILFIN can harm your unborn baby. Tell your healthcare provider right away if you become pregnant during treatment with IWILFIN or think you may be pregnant.Females who are able to become pregnant should have pregnancy test before starting treatment with IWILFIN.You should use effective birth control during treatment with IWILFIN and for week after the last dose.Males who have female partners who are able to become pregnant should use effective birth control during treatment with IWILFIN and for week after the last dose. Females who are able to become pregnant should have pregnancy test before starting treatment with IWILFIN.You should use effective birth control during treatment with IWILFIN and for week after the last dose.. Males who have female partners who are able to become pregnant should use effective birth control during treatment with IWILFIN and for week after the last dose.. are breastfeeding or plan to breastfeed. It is not known if IWILFIN passes into your breast milk. Do not breastfeed during treatment with IWILFIN and for week after the last dose.. Take IWILFIN exactly as your healthcare provider tells you to take it.. Take IWILFIN times day with or without food.. Swallow tablets whole. If you cannot swallow tablets whole, IWILFIN can be chewed, or crushed then mixed with soft food or liquid. If you are crushing IWILFIN tablets:IWILFIN can be crushed then mixed with tablespoons of soft food or liquid.Eat the entire mixture.If any crushed tablet pieces remain, mix with another small amount (about tablespoons) of soft food or liquid.Take all of the mixture within hour of mixing. Throw away any mixture left after hour. IWILFIN can be crushed then mixed with tablespoons of soft food or liquid.. Eat the entire mixture.. If any crushed tablet pieces remain, mix with another small amount (about tablespoons) of soft food or liquid.. Take all of the mixture within hour of mixing. Throw away any mixture left after hour.. If you miss dose of IWILFIN, take it as soon as you remember. If it is within hours of your next scheduled dose, skip the missed dose and take your next dose at your regular time.. If you vomit after taking dose, do not take an extra dose. Take your next dose at your regular time.. Low blood cell counts. IWILFIN can cause low blood cell counts and failure of your bone marrow to make enough platelets, red blood cells, or white blood cells. Your healthcare provider will monitor your blood cell counts before starting and during treatment with IWILFIN. Tell your healthcare provider right away if you develop symptoms of low blood cell counts, including:. fever (temperature 100.4F or higher). easy bruising or bleeding. blood in your urine or stools. feeling unusually tired or weak. shortness of breath. chills or shivering. Liver problems. Your healthcare provider will do blood tests before starting, every month for the first months, and regularly during treatment with IWILFIN to check your liver. Tell your healthcare provider if you develop symptoms of liver problems, including:. your skin or the white part of your eyes turns yellow (jaundice). dark or tea-colored urine. light-colored stools (bowel movements). nausea or vomiting. easy bruising or bleeding. loss of appetite. pain, aching, or tenderness on the right side of your stomach-area (abdomen). New or worsening hearing loss. Hearing loss is common during treatment with IWILFIN and can also be serious. Your healthcare provider will check your hearing before you start and during treatment with IWILFIN. Some people have needed to use hearing aids. Tell your healthcare provider right way if you get ringing in your ears or any new or worsening hearing loss.. ear infection. diarrhea. cough. sinus infection. pneumonia. upper respiratory tract infection. red and swollen eyes (pink eye). vomiting. stuffy, runny, itchy nose or sneezing (allergic rhinitis). fever. skin infection. urinary tract infection. Store IWILFIN at room temperature between 68F to 77F (20C to 25C).

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2)Renal Impairment: Reduce the dose in patients with estimated Glomerular Filtration Rate (eGFR) <30 mL/min. (2.3, 8.5, 12.3). 8.1Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ], IWILFIN can cause fetal harm when administered to 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 [see Data]. There are no available data on the use of IWILFIN in pregnant women. Advise pregnant women and females of reproductive potential of the potential risk to 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.. Data. Animal DataIn 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 to 7) resulted in reduced fetal body weights and an increase in the incidence of skeletal variations (presence of 14th rudimentary rib, 14th full rib, 27th presacral vertebrae) at 200 mg/kg/day [approximately 0.8 to times the recommended human dose of 1152 +- 384 mg/m2/day based on body surface area (BSA)]. In 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 to 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 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 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 to 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 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 to 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.. 8.2Lactation. Risk SummaryThere 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 IWILFIN and for week after the last dose.. 8.3Females and Males of Reproductive Potential. Based on animal data and its mechanism of action, IWILFIN can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating IWILFIN [see Use in Specific Populations (8.1)].. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with IWILFIN and for week after the last dose.. MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with IWILFIN and for week after the last dose.. 8.4Pediatric 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 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 median age of years (range: 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 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)].

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS. Myelosuppression: Monitor blood counts before and during treatment with IWILFIN. Withhold, reduce dose, or permanently discontinue based on severity. (5.1)Hepatotoxicity: Monitor liver function tests before and during treatment with IWILFIN. Withhold, reduce dose, or permanently discontinue based on severity. (5.2)Hearing Loss: Monitor hearing before and during treatment with IWILFIN. Withhold, reduce dose, or permanently discontinue based on severity. (5.3)Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.4, 8.1, 8.3) Myelosuppression: Monitor blood counts before and during treatment with IWILFIN. Withhold, reduce dose, or permanently discontinue based on severity. (5.1). Hepatotoxicity: Monitor liver function tests before and during treatment with IWILFIN. Withhold, reduce dose, or permanently discontinue based on severity. (5.2). Hearing Loss: Monitor hearing before and during treatment with IWILFIN. Withhold, reduce dose, or permanently discontinue based on severity. (5.3). Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.4, 8.1, 8.3) 5.1Myelosuppression. IWILFIN can cause myelosuppression. In the pooled safety population [see Adverse Reactions (6.1)], Grade or neutropenia occurred in 4.2% of patients. Febrile neutropenia occurred in 0.6% of patients. Bone marrow failure occurred in patient. Grade or thrombocytopenia occurred in 1.4% of patients. Grade 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 or events of increased alanine aminotransferase (ALT) occurred in 11% of patients. Grade or events of increased aspartate aminotransferase (AST) occurred in 6% of patients. Grade or 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 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)]. 5.3Hearing 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 or in 12% of patients. Tinnitus occurred in 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 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)]. 5.4Embryo-Fetal Toxicity. Based on findings from animal studies and its mechanism of action, IWILFIN can cause fetal harm when administered to 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 fetus. Advise females of reproductive potential to use effective contraception during treatment with IWILFIN and for week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with IWILFIN and for week after the last dose [see Use in Specific Populations (8.1, 8.3)].