iwilfin

5 WARNINGS 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 a fetus and to use effective contraception. ( 5.4 , 8.1 , 8.3 ) 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 ADVERSE 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) ] Most common adverse reactions (incidence ≥5%) are hearing loss, otitis media, pyrexia, pneumonia, and diarrhea. ( 6.1 ) Most common Grade 3 or 4 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 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%). Study 3b The 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 a partial response to prior multiagent, multimodality therapy including induction, consolidation, and anti-GD2 immunotherapy. Patients received 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 (N=85). Among patients who received IWILFIN, 93% were exposed for 6 months or longer and 89% were exposed for greater than one year. The median age of patients who received IWILFIN was 4 years (range: 1 to 17); 59% male; 85% White, 7% Black, 1% Asian, 8% Hispanic or Latino; 87% had International Neuroblastoma Staging System Stage 4 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 5 summarizes the adverse reactions in Study 3b. Table 5: Adverse Reactions (≥5%) in Patients with HRNB Who Received IWILFIN in Study 3b Adverse Reaction Severity as defined by CTCAE Version 4.03. IWILFIN (n=85) All Grades Grade 1 adverse events were not comprehensively collected in Study 3b. , No Grade 4 or 5 events were reported. (%) Grade 3 (%) Infections Otitis media 32 2.4 Sinusitis 13 0 Pneumonia 12 1.2 Upper respiratory tract infection 11 0 Conjunctivitis 11 0 Skin infection 7 4.7 Urinary tract infection 6 1.2 Gastrointestinal Disorders Diarrhea Includes colitis. 15 3.5 Vomiting 11 1.2 Respiratory Disorders Cough 15 0 Allergic rhinitis 11 0 General Disorders Pyrexia 11 1.2 Ear and Labyrinth Disorders Hearing loss 7 7 Clinically relevant adverse reactions in <5% of patients who received IWILFIN included rash, extremity pain, and alopecia. Table 6 summarizes the laboratory abnormalities in Study 3b. Table 6: Select Laboratory Abnormalities (≥1%) in Patients with HRNB Who Received IWILFIN in Study 3b Laboratory Abnormality Severity as defined by CTCAE Version 4.03. IWILFIN (n=85) All Grades Grade 1 adverse events were not comprehensively collected in Study 3b. , No Grade 5 events occurred. (%) Grade 3 or 4 (%) Chemistry Increased ALT 9 7 No Grade 4 events occurred. Increased AST 8 6 Increased alkaline phosphatase 4.7 2.4 Decreased potassium 2.4 2.4 Decreased glucose 2.4 1.1 Decreased sodium 2.4 2.4 Increased potassium 1.2 0 Increased glucose 1.2 0 Hematology Decreased neutrophils 9 8 Decreased hemoglobin 4.7 2.4 Decreased white blood cells 2.4 0 Decreased platelets 1.2 0

<table width="70%"><caption>Table 5: Adverse Reactions (&#x2265;5%) in Patients with HRNB Who Received IWILFIN in Study 3b</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" rowspan="2">Adverse Reaction<footnote ID="t4ft1">Severity as defined by CTCAE Version 4.03.</footnote></th><th styleCode="Rrule Botrule" colspan="2">IWILFIN (n=85)</th></tr><tr><th styleCode="Rrule" align="center">All Grades<footnote ID="t4ft2">Grade 1 adverse events were not comprehensively collected in Study 3b.</footnote>^,<footnote ID="t4ft3">No Grade 4 or 5 events were reported.</footnote> (%)</th><th styleCode="Rrule">Grade 3 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Infections</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Otitis media</td><td styleCode="Rrule">32</td><td styleCode="Rrule">2.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Sinusitis</td><td styleCode="Rrule">13</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pneumonia</td><td styleCode="Rrule">12</td><td styleCode="Rrule">1.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Conjunctivitis </td><td styleCode="Rrule">11</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Skin infection</td><td styleCode="Rrule">7</td><td styleCode="Rrule">4.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urinary tract infection</td><td styleCode="Rrule">6</td><td styleCode="Rrule">1.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea<footnote ID="t4ft4">Includes colitis.</footnote></td><td styleCode="Rrule">15</td><td styleCode="Rrule">3.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">11</td><td styleCode="Rrule">1.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Respiratory Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Allergic rhinitis</td><td styleCode="Rrule">11</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">General Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">11</td><td styleCode="Rrule">1.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Ear and Labyrinth Disorders</content></td></tr><tr><td styleCode="Lrule Rrule">Hearing loss</td><td styleCode="Rrule">7</td><td styleCode="Rrule">7</td></tr></tbody></table>

<table width="70%"><caption>Table 6: Select Laboratory Abnormalities (&#x2265;1%) in Patients with HRNB Who Received IWILFIN in Study 3b</caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" rowspan="2">Laboratory Abnormality<footnote ID="t5ft1">Severity as defined by CTCAE Version 4.03.</footnote></th><th styleCode="Rrule Botrule" colspan="2">IWILFIN (n=85)</th></tr><tr><th styleCode="Rrule" align="center">All Grades<footnote ID="t5ft2">Grade 1 adverse events were not comprehensively collected in Study 3b.</footnote>^,<footnote ID="t5ft3">No Grade 5 events occurred.</footnote> (%)</th><th styleCode="Rrule">Grade 3 or 4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Chemistry</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased ALT</td><td styleCode="Rrule">9</td><td styleCode="Rrule">7<footnote ID="t5ft4">No Grade 4 events occurred.</footnote></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased AST</td><td styleCode="Rrule">8</td><td styleCode="Rrule">6<footnoteRef IDREF="t5ft4"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased alkaline phosphatase</td><td styleCode="Rrule">4.7</td><td styleCode="Rrule">2.4<footnoteRef IDREF="t5ft4"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased potassium</td><td styleCode="Rrule">2.4</td><td styleCode="Rrule">2.4<footnoteRef IDREF="t5ft4"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased glucose</td><td styleCode="Rrule">2.4</td><td styleCode="Rrule">1.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased sodium</td><td styleCode="Rrule">2.4</td><td styleCode="Rrule">2.4<footnoteRef IDREF="t5ft4"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased potassium</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased glucose</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Hematology</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased neutrophils</td><td styleCode="Rrule">9</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased hemoglobin</td><td styleCode="Rrule">4.7</td><td styleCode="Rrule">2.4<footnoteRef IDREF="t5ft4"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased white blood cells</td><td styleCode="Rrule">2.4</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Decreased platelets</td><td styleCode="Rrule">1.2</td><td styleCode="Rrule">0</td></tr></tbody></table>