Chemical formula: C₁₉H₁₇F₆N₇O Molecular mass: 473.383 g/mol PubChem compound: 89683805
Based on animal embryo-fetal toxicity studies, enasidenib can cause fetal harm when administered to a pregnant woman. There are no available data on enasidenib use in pregnant women to inform a drug-associated 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.
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
Enasidenib administered to pregnant rats at a dose of 30 mg/kg twice daily during organogenesis (gestation days 6-17) was associated with maternal toxicity and adverse embryo-fetal effects including post-implantation loss, resorptions, decreased viable fetuses, lower fetal birth weights, and skeletal variations. These effects occurred in rats at approximately 1.6 times the clinical exposure at the recommended human daily dose of 100 mg/day.
In pregnant rabbits treated during organogenesis (gestation days 7-19), enasidenib was maternally toxic at doses equal to 5 mg/kg/day or higher (exposure approximately 0.1 to 0.6 times the steady state clinical exposure at the recommended daily dose) and caused spontaneous abortions at 5 mg/kg/day (exposure approximately 0.1 times the steady state clinical exposure at the recommended daily dose).
There are no data on the presence of enasidenib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with enasidenib and for at least 2 months after the last dose.
Carcinogenicity studies have not been performed with enasidenib.
Enasidenib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Enasidenib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay, or in an in vivo rat bone marrow micronucleus assay.
Fertility studies in animals have not been conducted with enasidenib. In repeat-dose toxicity studies with twice daily oral administration of enasidenib in rats up to 90-days in duration, changes were reported in male and female reproductive organs including seminiferous tubular degeneration, hypospermia, atrophy of the seminal vesicle and prostate, decreased corpora lutea and increased atretic follicles in the ovaries, and atrophy in the uterus.
The following clinically significant adverse reactions are described elsewhere in the labeling:
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 enasidenib 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 enasidenib was 4.3 months (range 0.3 to 23.6). The 30-day and 60-day mortality rates observed with enasidenib 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 enasidenib 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:
| Enasidenib (100 mg daily) N=214 | ||
|---|---|---|
| Body System Adverse Reaction | All Grades N=214 n (%) | ≥Grade 3 N=214 n (%) |
| Gastrointestinal Disordersa | ||
| 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 enasidenib treatment can be associated with other commonly reported events such as abdominal pain, and weight decreased.
b Tumor lysis syndrome observed with enasidenib 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
| enasidenib (100 mg daily) N=214 | ||
|---|---|---|
| Parametera | 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 enasidenib 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).
Enasidenib 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 enasidenib permanently due to hyperbilirubinemia.
Enasidenib can induce myeloid proliferation resulting in a rapid increase in white blood cell count.
Enasidenib can induce myeloid proliferation resulting in a rapid reduction in tumor cells which may pose a risk for tumor lysis syndrome.
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