IDHIFA Film-coated tablet Ref.[10218] Active ingredients: Enasidenib

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 females of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 2 months 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 2 months 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)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Differentiation Syndrome [see Warnings and Precautions (5.1)]

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.

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:

^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

^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 [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.

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 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.

Data

Animal Data

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).

Risk Summary

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 IDHIFA and for at least 2 months after the last dose.

Pregnancy Testing

Based on animal embryo-fetal toxicity studies, IDHIFA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Obtain a pregnancy test on females of reproductive potential prior to starting treatment with IDHIFA.

Contraception

Females

Advise females of reproductive potential to avoid becoming pregnant while receiving IDHIFA. Advise females of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 2 months after the last dose. Coadministration of IDHIFA may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 2 months after the last dose of IDHIFA.

Infertility

Based on findings in animals, IDHIFA may impair fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].

Safety and effectiveness in pediatric patients have not been established.

No dosage adjustment is required for IDHIFA based on age. In the clinical study, 61% of 214 patients were aged 65 years or older, while 24% were older than 75 years. No overall differences in effectiveness or safety were observed between patients aged 65 years or older and younger patients.