WARNING: DIFFERENTIATION SYNDROME Patients treated with IDHIFA have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, lymphadenopathy, bone pain, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . WARNING: DIFFERENTIATION SYNDROME See full prescribing information for complete boxed warning. Patients treated with IDHIFA have experienced symptoms of differentiation syndrome, which can be fatal if not treated. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution ( 5.1 , 6.1 ).
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity : IDHIFA can cause fetal harm. Advise patients of the potential risk to a fetus and use effective contraception ( 5.2 , 8.1 , 8.3 ). 5.1 Differentiation Syndrome In the clinical trial, 14% of patients treated with IDHIFA experienced differentiation syndrome, which may be life-threatening or fatal if not treated. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. While there is no diagnostic test for differentiation syndrome, symptoms in patients treated with IDHIFA included acute respiratory distress represented by dyspnea and/or hypoxia (68%) and need for supplemental oxygen (76%); pulmonary infiltrates (73%) and pleural effusion (45%); renal impairment (70%); fever (36%); lymphadenopathy (33%); bone pain (27%); peripheral edema with rapid weight gain (21%); and pericardial effusion (18%). Hepatic, renal, and multi-organ dysfunction have also been observed. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, in as early as 1 day and up to 5 months after IDHIFA initiation. If differentiation syndrome is suspected, initiate oral or intravenous corticosteroids (e.g., dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt IDHIFA until signs and symptoms are no longer severe [see Dosage and Administration (2.3) ] . Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended. 5.2 Embryo-Fetal Toxicity Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when administered to a pregnant woman. In animal embryo-fetal toxicity studies, enasidenib caused embryo-fetal toxicities starting at 0.1 times the steady state clinical exposure based on the area under the concentration-time curve (AUC) at the recommended human dose. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective non‑hormonal contraception during treatment with IDHIFA and for 2 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for 2 months 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: • Differentiation Syndrome [see Warnings and Precautions (5.1) ] The most common adverse reactions (≥20%) are nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Bristol Myers Squibb at 1-800-721-5072 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 the rates observed in practice. The safety evaluation of single-agent IDHIFA is based on 214 patients with relapsed or refractory AML who were assigned to receive 100 mg daily [see Clinical Studies (14.1) ] . The median duration of exposure to IDHIFA was 4.3 months (range 0.3 to 23.6). The 30-day and 60-day mortality rates observed with IDHIFA were 4.2% (9/214) and 11.7% (25/214), respectively. Serious adverse reactions were reported in 77.1% of patients. The most frequent serious adverse reactions (≥2%) were leukocytosis (10%), diarrhea (6%), nausea (5%), vomiting (3%), decreased appetite (3%), tumor lysis syndrome (5%), and differentiation syndrome (8%). Differentiation syndrome events characterized as serious included pyrexia, renal failure acute, hypoxia, respiratory failure, and multi-organ failure. Overall, 92 of 214 patients (43%) required a dose interruption due to an adverse reaction; the most frequent adverse reactions leading to dose interruption were differentiation syndrome (4%) and leukocytosis (3%). Ten of 214 patients (5%) required a dose reduction due to an adverse reaction; no adverse reaction required dose reduction in more than 2 patients. Thirty-six of 214 patients (17%) permanently discontinued IDHIFA due to an adverse reaction; the most frequent adverse reaction leading to permanent discontinuation was leukocytosis (1%). The most common adverse reactions (≥20%) of any grade were nausea, vomiting, diarrhea, elevated bilirubin and decreased appetite. Adverse reactions reported in the trial are shown in Table 2. Table 2: Adverse Reactions Reported in ≥10% (Any Grade) or ≥3% (Grade 3-5) of Patients with Relapsed or Refractory AML a Gastrointestinal disorders observed with IDHIFA treatment can be associated with other commonly reported events such as abdominal pain, and weight decreased. b Tumor lysis syndrome observed with IDHIFA treatment can be associated with commonly reported uric acid increased. c Differentiation syndrome can be associated with other commonly reported events such as respiratory failure, dyspnea, hypoxia, pyrexia, peripheral edema, rash, or renal insufficiency. IDHIFA (100 mg daily) N=214 Body System Adverse Reaction All Grades N=214 n (%) ≥Grade 3 N=214 n (%) Gastrointestinal Disorders a Nausea 107 (50) 11 (5) Diarrhea 91 (43) 17 (8) Vomiting 73 (34) 4 (2) Metabolism and Nutrition Disorders Decreased appetite 73 (34) 9 (4) Tumor lysis syndrome b 13 (6) 12 (6) Blood and Lymphatic System Disorders Differentiation syndrome c 29 (14) 15 (7) Noninfectious leukocytosis 26 (12) 12 (6) Nervous System Disorders Dysgeusia 25 (12) 0 (0) Other clinically significant adverse reactions occurring in <10% of patients included: • Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary edema, acute respiratory distress syndrome Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory AML are shown in Table 3. Table 3: Most Common (≥20%) New or Worsening Laboratory Abnormalities Reported in Patients with Relapsed or Refractory AML IDHIFA (100 mg daily) N=214 Parameter a All Grades (%) Grade ≥3 (%) a Includes abnormalities occurring up to 28 days after last IDHIFA dose, if new or worsened by at least one grade from baseline, or if baseline was unknown. The denominator varies based on data collected for each parameter (N=213 except phosphorous N=209). Total bilirubin increased 81 15 Calcium decreased 74 8 Potassium decreased 41 15 Phosphorus decreased 27 8 Elevated Bilirubin IDHIFA may interfere with bilirubin metabolism through inhibition of UGT1A1 [see Clinical Pharmacology (12.3) ] . Thirty-seven percent of patients (80/214) experienced total bilirubin elevations ≥2 x ULN at least one time. Of those patients who experienced total bilirubin elevations ≥2 x ULN, 35% had elevations within the first month of treatment, and 89% had no concomitant elevation of transaminases or other severe adverse events related to liver disorders. No patients required a dose reduction for hyperbilirubinemia; treatment was interrupted in 3.7% of patients, for a median of 6 days. Three patients (1.4%) discontinued IDHIFA permanently due to hyperbilirubinemia. Noninfectious Leukocytosis IDHIFA can induce myeloid proliferation resulting in a rapid increase in white blood cell count. Tumor Lysis Syndrome IDHIFA can induce myeloid proliferation resulting in a rapid reduction in tumor cells which may pose a risk for tumor lysis syndrome. Other Clinical Trials Experience The following adverse reactions occurred in other clinical trials of IDHIFA at the recommended dosage: neutropenia, thrombocytopenia, anemia, stomatitis, renal failure, fatigue, dyspnea, and QT prolongation.
adverse reactions table
<table width="100%"><caption>Table 2: Adverse Reactions Reported in ≥10% (Any Grade) or ≥3% (Grade 3-5) of Patients with Relapsed or Refractory AML</caption><col width="59%"/><col width="21%"/><col width="21%"/><tfoot><tr><td align="left" colspan="3" valign="top"><sup>a</sup> Gastrointestinal disorders observed with IDHIFA treatment can be associated with other commonly reported events such as abdominal pain, and weight decreased. <sup>b</sup> Tumor lysis syndrome observed with IDHIFA treatment can be associated with commonly reported uric acid increased. <sup>c</sup> Differentiation syndrome can be associated with other commonly reported events such as respiratory failure, dyspnea, hypoxia, pyrexia, peripheral edema, rash, or renal insufficiency.</td></tr></tfoot><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">IDHIFA (100 mg daily) N=214</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Body System</content> Adverse Reaction</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">All Grades N=214 n (%)</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">≥Grade 3 N=214 n (%)</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content><sup>a</sup></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>107 (50)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>11 (5)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>91 (43)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>17 (8)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>73 (34)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4 (2)</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolism and Nutrition Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Decreased appetite</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>73 (34)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>9 (4)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Tumor lysis syndrome<sup>b</sup></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>13 (6)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12 (6)</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Blood and Lymphatic System Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Differentiation syndrome<sup>c</sup></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>29 (14)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>15 (7)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Noninfectious leukocytosis</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>26 (12)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12 (6)</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Dysgeusia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>25 (12)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0 (0)</paragraph></td></tr></tbody></table>
adverse reactions table
<table width="100%"><caption>Table 3: Most Common (≥20%) New or Worsening Laboratory Abnormalities Reported in Patients with Relapsed or Refractory AML</caption><col width="59%"/><col width="21%"/><col width="21%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">IDHIFA (100 mg daily) N=214</content></th></tr><tr><th align="left" styleCode="Rrule Lrule Botrule " valign="top"><content styleCode="bold">Parameter<sup>a</sup></content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">All Grades (%)</content></th><th align="center" styleCode="Rrule Botrule " valign="top"><content styleCode="bold">Grade ≥3 (%)</content></th></tr></thead><tfoot><tr><td align="left" colspan="3" valign="top"><sup>a</sup> Includes abnormalities occurring up to 28 days after last IDHIFA dose, if new or worsened by at least one grade from baseline, or if baseline was unknown. The denominator varies based on data collected for each parameter (N=213 except phosphorous N=209).</td></tr></tfoot><tbody><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Total bilirubin increased</paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>81</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Calcium decreased</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>74</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Potassium decreased</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>41</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>15</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Phosphorus decreased</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>27</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>8</paragraph></td></tr></tbody></table>