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Safety Profile

IDHIFA® OFFERS A DIFFERENT SAFETY PROFILE IN R/R AML

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

Body system
AR		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 syndrome (TLS)b13 (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.

bTLS 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.

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

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 phosphorus [N=209]).

The median duration of exposure to IDHIFA® was 4.3 months (range, 0.3 to 23.6).

IDHIFA® demonstrated 30-day and 60-day mortality rates of 4.2% (9/214) and 11.7% (25/214), respectively.

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

DOSE MODIFICATIONS IN THE CLINICAL TRIAL

DOSE INTERRUPTION

43%

(n=92/214)

43% of patients experienced an AR leading to a dose interruption

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

DOSE REDUCTION

5%

(n=10/214)

5% of patients had a dose reduction due to an AR

  • No AR required dose reduction in more than 2 patients

THERAPY DISCONTINUATION

17%

(n=36/214)

17% of patients permanently discontinued therapy due to an AR

  • The most common reason for discontinuation was leukocytosis (1%)

ADDITIONAL ANALYSIS: The Frequency of ARs Over Time

ARs REPORTED IN ≥10% (ANY GRADE) OR ≥3% (GRADES 3-5) OF PATIENTS WITH R/R AML1

35% FREQUENCY OF ARs 30 % 25% 20 % 15 % 10 % 5% 0% Nausea Cycle 1 N=168 Cycle 3 N=214 N=100 Cycle 6 N=193 Cycle 2 N=121 Cycle 5 N=146 Cycle 4 Diarrhea Vomiting Decreased appetite Tumor lysis syndrome Differentiation syndrome Noninfectious leukocytosis Dysgeusia

Differentiation Syndrome

DIFFERENTIATION SYNDROME MAY OCCUR WITH IDHIFA®

Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. It may be life-threatening or fatal if not treated.

14%
14% of patients experienced differentiation syndrome (n=29/214)
7%
7% of patients experienced ≥Grade 3 differentiation syndrome
(n=15/214)
4%
4% of patients required dose interruption due to differentiation syndrome

For appropriate patient management,
IT IS IMPORTANT TO RECOGNIZE AND INITIATE TREATMENT FOR DIFFERENTIATION SYNDROME

Differentiation syndrome

Symptoms observed in patients treated with IDHIFA®

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, and need for supplemental oxygen
  • Pulmonary infiltrates and pleural effusion
  • Renal impairment
  • Fever
  • Lymphadenopathy
  • Bone pain
  • Peripheral edema with rapid weight gain
  • Pericardial effusion
  • Hepatic, renal, and multi-organ dysfunction

Initial management

  • If differentiation syndrome is suspected, initiate oral or intravenous corticosteroids (eg, dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until improvement
  • 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

Subsequent management

  • Taper corticosteroids only after resolution of symptoms
  • Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment
  • Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended

Differentiation syndrome has been observed with and without concomitant hyperleukocytosis in as early as 1 day and up to 5 months after IDHIFA® initiation

Noninfectious leukocytosis

WBC count

>30x109/L

Initial management

  • Initiate treatment with hydroxyurea, as per standard institutional practices

Subsequent management

  • Interrupt IDHIFA® if leukocytosis is not improved with hydroxyurea
  • Then resume IDHIFA® at 100 mg daily when WBC is <30x109/L

WATCH AN AML EXPERT DISCUSS DIFFERENTIATION SYNDROME WITH IDHIFA®

Explore important topics in managing patients who have R/R AML with an IDH2 mutation receiving IDHIFA®, including diagnosing and treating differentiation syndrome and other adverse events.

Dr Harry Erba and Marilyn Pritchard, RN have been paid by Bristol Myers Squibb to participate in this video.

Additional Warnings, Precautions, & ARs

ADDITIONAL WARNINGS, PRECAUTIONS, AND ARs

SELECTED WARNINGS AND PRECAUTIONS

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 2 months 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

SELECTED ARs

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) were 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 WBC count
12%

(n=26/214)

12% of patients experienced leukocytosis

Tumor lysis syndrome

  • IDHIFA® can induce myeloid proliferation resulting in a rapid reduction in tumor cells, which may pose a risk for TLS
6%

(n=13/214)

6% of patients experienced TLS

Next: Dosing

Indication

IDHIFA® (enasidenib) is indicated for the treatment of adult patients with relapsed or refractory (R/R) 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, which may be life-threatening or fatal if not treated. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, in as early as 1 day and up to 5 months after IDHIFA initiation. Symptoms in patients treated with IDHIFA included acute respiratory distress represented by dyspnea and/or hypoxia and need for supplemental oxygen; pulmonary infiltrates and pleural effusion; renal impairment; fever; lymphadenopathy; bone pain; peripheral edema with rapid weight gain; and pericardial effusion. Hepatic, renal, and multi-organ dysfunction have also been observed. 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 2 months 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 children, advise women not to breastfeed during treatment with IDHIFA and for at least 2 months after the last dose.

Please see full Prescribing Information, including Boxed WARNING.

Reference:

  • Data on file, Celgene Corporation. Summit, New Jersey.

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Celgene Commercial Co-pay Program Terms and Conditions

Eligibility

Patients must meet the following criteria to enroll:

  • Covered by commercial or private insurance
  • Reside in the United States or US territory
  • Not participating in a federal or state-funded healthcare program, including, but not limited to, Medicare (Parts B, C, and D) or Medicaid, Medigap, CHAMPUS, VA, DOD, or Tricare
  • Gross annual household income must not exceed $100,000
    • Gross household income is the total income before income tax deductions from all people living in your household. Gross income refers not only to the salaries and benefits received, but also to receipts from any personal business, investments, dividends, and other income

Program Benefits

  • For Celgene oral hematology products, Celgene provides assistance to reduce the co-pay of eligible patients to $25 per prescription with a maximum benefit of $10,000 per enrollment period
  • For Celgene IV products, the Program will cover the co-pay for each prescription of a Celgene product up to a maximum of $10,000 per enrollment period
    • In order to receive the Program benefits for a Celgene IV product, patients or their providers must submit an Explanation of Benefits (EOB) form
  • Patients are responsible for any costs that exceed the Program’s $10,000 maximum
  • The Program will not cover, and shall not be applied toward, the cost of any dosing procedure, any other healthcare provider service or supply charges or other treatment costs, or any costs associated with a hospital stay

Program Timing

  • If eligible, patients will be enrolled from the date of enrollment through the end of the then current calendar year

Additional Terms and Conditions of the Celgene Commercial Co-pay Programs

  • Patients, pharmacists, and healthcare providers must not seek reimbursement from health insurance or any third party for any part of the benefit received by the patient through this Program. Patients must not seek reimbursement from any health savings, flexible spending, or other healthcare reimbursement accounts for the amount of assistance received from the Program
  • Acceptance of this offer confirms that this offer is consistent with your insurance and that you will report the value of the co-pay assistance you receive as may be required by your insurance provider
  • Only valid in the United States and US territories; this offer is void where prohibited by law, taxed or restricted. Absent a change in Massachusetts law, effective July 1, 2019, Massachusetts residents will no longer be eligible to participate in this Program
  • The Program benefits are nontransferable
  • Acceptance in this Program is not conditioned on any past, present, or future purchase, including additional doses
  • The Program cannot be combined with any other coupon, rebate, voucher, free trial, or similar offer
  • The Program is not insurance
  • Celgene reserves the right to rescind, revoke, or amend this Program at any time without notice

© 2017 Celgene Corporation 06/17 US-CELG170216

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