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Safety

Warnings and Precautions

Differentiation syndrome

Differentiation syndrome is caused by 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

14% of patients (29/214) treated with IDHIFA experienced differentiation syndrome.

  • 7% of patients (15/214) experienced ≥Grade 3 events
  • 4% of patients required a dose interruption of IDHIFA due to differentiation syndrome

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 untreated, differentiation syndrome may be life-threatening or fatal.

Management of differentiation syndrome

At first suspicion of differentiation syndrome:

  • 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
  • Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended

Embryo-fetal Toxicity

Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when administered to a pregnant woman.

  • Advise females of reproductive potential and males with female partners of reproductive potential to use contraception during treatment 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

Adverse Reactions

The safety evaluation of single-agent IDHIFA is based on 214 patients with R/R 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 (ARs) (≥20%) of any grade were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite.

  • Serious ARs 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, 43% of patients (92/214) required a dose interruption due to an AR.

  • The most common ARs leading to dose interruption were differentiation syndrome (4%) and leukocytosis (3%)

5% of patients (10/214) required a dose reduction due to an AR.

  • No AR required dose reduction in more than 2 patients

17% of patients (36/214) permanently discontinued IDHIFA due to an AR.

  • The most common AR leading to permanent discontinuation was leukocytosis (1%)

Adverse Reactions Reported in ≥10% (Any Grade) or ≥3% (Grade 3-5) of Patients With R/R AML

Body system
Adverse reaction

All grades
N=214 (%)

≥Grade 3
N=214 (%)

Gastrointestinal disordersa
Nausea107 (50)11 (5)
Diarrhea91 (43)17 (8)
Vomiting73 (34)4 (2)
Metabolism and nutrition disorders
Decreased appetite73 (34)9 (4)
Tumor lysis syndromeb13 (6)12 (6)
Blood and lymphatic system disorders
Differentiation syndromec29 (14)15 (7)
Noninfectious leukocytosis26 (12)12 (6)
Nervous system disorders
Dysgeusia25 (12)0 (0)

aGastrointestinal disorders observed with IDHIFA treatment can be associated with other commonly reported events such as abdominal pain and weight decrease.

bTumor lysis syndrome observed with IDHIFA treatment can be associated with commonly reported uric acid increase.

cDifferentiation 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 ARs occurring in ≤10% of patients included Respiratory, Thoracic, and Mediastinal Disorders (pulmonary edema, acute respiratory distress syndrome).

Most Common (≥20%) New or Worsening Laboratory
Abnormalities Reported in Patients with R/R Aml (N=214)

ParameteraAll grades (%)≥Grade 3 (%)
Total bilirubin increased8115
Calcium decreased748
Potassium decreased4115
Phosphorus decreased278

aIncludes abnormalities occurring up to 28 days after last IDHIFA dose, if new or worsened by at least 1 grade from baseline, or if baseline was unknown. The denominator varies based on data collected for each parameter (N=213 except phosphorous N=209).

ADDITIONAL ADVERSE REACTIONS

ELEVATED BILIRUBIN

IDHIFA may interfere with bilirubin metabolism through inhibition of UGT1A1.

  • Total bilirubin elevations (≥2x upper limit of normal [ULN]) at least one time was observed in 37% of patients (80/214)
    • Of these patients, 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 and treatment was interrupted in 3.7% of patients for a median of 6 days.
  • Additionally, 1.4% of patients (3/214) discontinued IDHIFA permanently due to hyperbilirubinemia

Noninfectious leukocytosis

  • IDHIFA can induce myeloid proliferation resulting in a rapid increase in white blood cell (WBC) count

TUMOR LYSIS SYNDROME (TLS)

  • IDHIFA can induce myeloid proliferation resulting in a rapid reduction in tumor cells which may pose a risk for TLS

IDHIFA Dosing & Administration

IDHIFA offers daily oral therapy

idhifa dosing 100 mg

Starting dose:
IDHIFA 100 mg once daily

administering idhifa

Swallow whole with a cup of water.
Do not split or crush the tablets.

idhifa oral tablets

Administer IDHIFA tablets orally about the same time each day with or without food.

  • IDHIFA should be taken until disease progression or unacceptable toxicity
  • 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
  • Assess blood counts and blood chemistries for leukocytosis and TLS 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

For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response

Dosage Modifications for Toxicities

Adverse reactionRecommended action
Differentiation syndrome
  • If differentiation syndrome is suspected, administer systemic corticosteroids and initiate hemodynamic monitoring
  • 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
  • Resume IDHIFA when signs and symptoms improve to Grade 2a or lower
Noninfectious leukocytosis (WBC count greater than 30 x 109/L)
  • 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 109/L
Elevation of bilirubin greater than 3x ULN sustained for ≥2 weeks without elevated transaminases or other hepatic disorders
  • Reduce IDHIFA dose to 50 mg daily
  • Resume IDHIFA at 100 mg daily if bilirubin elevation resolves to less than 2x ULN
Other Grade 3a or higher toxicity considered related to treatment including TLS
  • Interrupt IDHIFA until toxicity resolves to Grade 2a or lower
  • Resume IDHIFA at 50 mg daily; may increase to 100 mg daily if toxicities resolve to Grade 1a or lower
  • If Grade 3a or higher toxicity recurs, discontinue IDHIFA

a Grade 1 is mild, Grade 2 is moderate, Grade 3 is serious, Grade 4 is life-threatening.

There are no contraindications to IDHIFA.

Indication

IDHIFA® (enasidenib) 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.

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Important Safety 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.

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WARNINGS AND PRECAUTIONS

Differentiation Syndrome: See Boxed WARNING. In the clinical trial, 14% of patients treated with IDHIFA experienced differentiation syndrome. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, as early as 10 days and at up to 5 months after IDHIFA initiation. If differentiation syndrome is suspected, initiate systemic corticosteroids and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Differentiation syndrome symptoms may recur with premature discontinuation of corticosteroids. 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. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended.

Embryo-Fetal Toxicity: Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential and 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. 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.

ADVERSE REACTIONS

  • The most common adverse reactions (≥20%) included total bilirubin increased (81%), calcium decreased (74%), nausea (50%), diarrhea (43%), potassium decreased (41%), vomiting (34%), decreased appetite (34%), and phosphorus decreased (27%)
  • The most frequently reported ≥Grade 3 adverse reactions (≥5%) included total bilirubin increased (15%), potassium decreased (15%), phosphorus decreased (8%), calcium decreased (8%), diarrhea (8%), differentiation syndrome (7%), non-infectious leukocytosis (6%), tumor lysis syndrome (6%), and nausea (5%)
  • 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

LACTATION

Many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with IDHIFA and for at least 1 month after the last dose.

Please see full Prescribing Information, including Boxed WARNING.

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