IDHIFA ® ( enasidenib ) tablets , for oral use The following is a Brief Summary ; refer to full Prescribing Information for complete product information .
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 )].
1 INDICATIONS AND USAGE 1.1 Acute Myeloid Leukemia IDHIFA is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia ( AML ) with an isocitrate dehydrogenase-2 ( IDH2 ) mutation as detected by an FDA-approved test .
2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Select patients for the treatment of AML with IDHIFA based on the presence of IDH2 mutations in the blood or bone marrow [ see Indications and Usage ( 1.1 )]. Information on FDA-approved tests for the detection of IDH2 mutations in AML is available at http :// www . fda . gov / CompanionDiagnostics .
2.2 Recommended Dosage The recommended starting dose of IDHIFA is 100 mg taken orally once daily with or without food until disease progression or unacceptable toxicity . For patients without disease progression or unacceptable toxicity , treat for a minimum of 6 months to allow time for clinical response .
Do not split or crush IDHIFA tablets . Administer IDHIFA tablets orally about the same time each day . If a dose of IDHIFA is vomited , missed , or not taken at the usual time , administer the dose as soon as possible on the same day , and return to the normal schedule the following day .
2.3 Monitoring and Dosage Modifications for Toxicities Assess blood counts and blood chemistries for leukocytosis and tumor lysis syndrome prior to the initiation of IDHIFA and monitor at a minimum of every 2 weeks for at least the first 3 months during treatment . Manage any abnormalities promptly [ see Adverse Reactions ( 6.1 )].
Interrupt dosing or reduce dose for toxicities . See Table 1 for dosage modification guidelines . Table 1 : Dosage Modifications for IDHIFA-Related Toxicities
Adverse Reaction
Recommended Action
• Differentiation syndrome
• Noninfectious leukocytosis ( white blood cell [ WBC ] count greater than 30 x 10 9 / L )
• Elevation of bilirubin greater than 3 times the upper limit of normal ( ULN ) sustained for ≥2 weeks without elevated transaminases or other hepatic disorders
• Other Grade 3 * or higher toxicity considered related to treatment including tumor lysis syndrome
• If differentiation syndrome is suspected , administer systemic corticosteroids and initiate hemodynamic monitoring [ see Warnings and Precautions ( 5.1 )].
• Interrupt IDHIFA if severe pulmonary symptoms requiring intubation or ventilator support , and / or renal dysfunction persist for more than 48 hours after initiation of corticosteroids [ see Warnings and Precautions ( 5.1 )].
• Resume IDHIFA when signs and symptoms improve to Grade 2 * or lower .
• Initiate treatment with hydroxyurea , as per standard institutional practices .
• Interrupt IDHIFA if leukocytosis is not improved with hydroxyurea , and then resume IDHIFA at 100 mg daily when WBC is less than 30 x 10 9 / L .
• Reduce IDHIFA dose to 50 mg daily .
• Resume IDHIFA at 100 mg daily if bilirubin elevation resolves to less than 2 x ULN .
• Interrupt IDHIFA until toxicity resolves to Grade 2 * or lower .
• Resume IDHIFA at 50 mg daily ; may increase to 100 mg daily if toxicities resolve to Grade 1 * or lower .
• If Grade 3 * or higher toxicity recurs , discontinue IDHIFA . * Grade 1 is mild , Grade 2 is moderate , Grade 3 is serious , Grade 4 is life-threatening .
4 CONTRAINDICATIONS None .
5 WARNINGS AND PRECAUTIONS 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 , and as early as 10 days and at 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 females of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 1 month after the last dose of IDHIFA . Advise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 1 month after the last dose of IDHIFA . Pregnant women , patients becoming pregnant while receiving IDHIFA , or male patients with pregnant female partners should be apprised of the potential risk to the fetus [ see Use in Specific Populations ( 8.1 , 8.3 )].
6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling :
• Differentiation Syndrome [ see Warnings and Precautions ( 5.1 )]
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 . 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 .
The most common adverse reactions ( ≥20 %) of any grade were nausea , vomiting , diarrhea , elevated bilirubin and decreased appetite .
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 common 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 common adverse reaction leading to permanent discontinuation was leukocytosis ( 1 %).
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
IDHIFA ( 100 mg daily ) N = 214
Body System All Grades ≥Grade 3 Adverse Reaction N = 214 N = 214 n (%) 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 ) 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 .
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 (%) (%)
Total bilirubin increased 81 15 Calcium decreased 74 8 Potassium decreased 41 15 Phosphorus decreased 27 8 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 ).
Elevated Bilirubin IDHIFA may interfere with bilirubin metabolism through inhibition of UGT1A1 . 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 .
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on animal embryo-fetal toxicity studies , IDHIFA can cause fetal harm when administered to a pregnant woman . There are no available data on IDHIFA use in pregnant women to inform a drugassociated risk of major birth defects and miscarriage . In animal embryo-fetal toxicity studies , oral administration of enasidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 0.1 times the steady state clinical exposure based on the AUC at the recommended human dose ( see Data ). If this drug is used during pregnancy , or if the patient becomes pregnant while taking this drug , advise the patient of the potential risk to a fetus .