INDICATION

INREBIC® (fedratinib) is indicated for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF).

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Encephalopathy

Cases of encephalopathy, including Wernicke’s encephalopathy (WE), in the INREBIC® clinical development program1

  • In the clinical development program of INREBIC®, which included 608 patients, serious and fatal cases of encephalopathy, including WE, occurred in INREBIC®-treated patients. Serious cases were reported in 1.3% (8/608) of patients treated with INREBIC® in clinical trials and 0.16% (1/608) of cases were fatal
  • Encephalopathy, including WE, is a neurologic emergency that can be fatal
  • WE is attributable to thiamine (vitamin B1) deficiency
  • Signs and symptoms of WE may include ataxia, mental status changes, and ophthalmoplegia (eg, nystagmus, diplopia)
  • Any change in mental status, confusion, or memory impairment should raise concern for potential encephalopathy, including WE, and prompt a full evaluation including a neurologic examination, assessment of thiamine levels, and imaging

Management of encephalopathy, including WE

Assess at treatment initiation

  • Assess thiamine levels prior to starting INREBIC®
  • Do not start INREBIC® in patients with thiamine deficiency

Monitor during treatment

  • Assess thiamine levels periodically during treatment and as clinically indicated
  • Monitor for signs and symptoms of WE, which may include ataxia, mental status changes, and ophthalmoplegia (eg, nystagmus, diplopia)

Intervene immediately if thiamine deficient or if encephalopathy is suspected

  • Do not start INREBIC® in patients with thiamine deficiency; replete thiamine prior to treatment initiation and during treatment if thiamine levels are low
  • If encephalopathy is suspected, immediately discontinue treatment with INREBIC® and initiate parenteral thiamine treatment
  • Monitor until symptoms resolve or improve and thiamine levels normalize

Study Design

INREBIC® was studied in patients with similar characteristics to those seen in practice1,2

A robust phase-3 study (JAKARTA)

A double-blind, randomized, placebo-controlled, phase-3 study (N=289) in patients not previously treated with a JAK inhibitor with intermediate-2 or high-risk primary or secondary myelofibrosis

Randomized 1:1:1

Baseline characteristics overview

ET, essential thrombocythemia; IPSS, International Prognostic Scoring System; JAK, Janus-associated kinase; PV, polycythemia vera; qd, once daily.

The recommended daily dose is 400 mg; therefore, only the 400‑mg arm will be shown relative to placebo

Efficacy

INREBIC® provided a powerful spleen response vs placebo1

Proportion of patients with SVR ≥35% from baseline at the end of cycle 6 as measured by MRI or CT with a follow-up scan 4 weeks latera

P<0.0001

Graph showing the percent of patients with SVR greater than or equal to 35 percent at end of cycle 6 with follow-up scan 4 weeks later Graph showing the percent of patients with SVR greater than or equal to 35 percent at end of cycle 6 with follow-up scan 4 weeks later

Based on Kaplan-Meier estimates, the median duration of spleen response was 18.2 months for the INREBIC® 400-mg group

aIntent-to-treat (ITT) population.

Percent change in spleen volume from baseline at the end of cycle 6 as measured by MRI or CT for each patienta

Graph showing percent change in spleen volume for each patient at end of cycle 6 Graph showing percent change in spleen volume for each patient at end of cycle 6

aPatients with available percent change in spleen volume at the end of cycle 6.

INREBIC® demonstrated a statistically significant reduction in TSS vs placebo1

Proportion of patients with ≥50% reduction in TSS from baseline at the end of cycle 6 as measured by the MFSAFa

P<0.0001

Graph showing the percentage of patients with a greater than or equal to 50 percent reduction in TSS at end of cycle 6 Graph showing the percentage of patients with a greater than or equal to 50 percent reduction in TSS at end of cycle 6

aIn symptom-evaluable population.

Percent change in TSS from baseline at the end of cycle 6 as measured by the MFSAF for each patienta

graph showing percent change in TSS for each patient at end of cycle 6 graph showing percent change in TSS for each patient at end of cycle 6

aPatients with available percent change in TSS at the end of cycle 6 as measured by the modified MFSAF v2.0 diary.

The modified MFSAF v2.0 is a patient diary capturing the 6 core symptoms of MF: night sweats, itching, abdominal discomfort, early satiety, pain under the ribs on the left side, and bone or muscle pain.

The NCCN Guidelines® include fedratinib3

NCCN Clinical Practice Guidelines in Oncology
(NCCN Guidelines®)* recommend fedratinib as initial therapy (category 2B) for

  • Patients with intermediate-2 or high-risk myelofibrosis
  • AND platelets ≥50 x 109/L
  • AND who are transplant ineligible

*NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

INREBIC® in patients previously treated with ruxolitinib (JAKARTA2)2

Limitations

JAKARTA2, a phase-2, single-arm, open-label study, was prematurely terminated, which impacts the interpretability of the data. No conclusions regarding the benefits or risks of fedratinib in patients who are resistant or intolerant to ruxolitinib can be established based on this study. These data are not included in the Prescribing Information.

JAKARTA2 study design and select patient characteristics

  • Single-arm, open-label, phase-2 study in 97 primary or secondary myelofibrosis patients resistant or intolerant to ruxolitinib per investigator assessment

  • The primary endpoint was the proportion of patients achieving ≥35% spleen volume reduction at the end of cycle 6 as measured by MRI or CT

  • Median exposure to ruxolitinib prior to enrollment in study was 10.7 months

  • Median exposure to INREBIC® during enrollment in study was 24 weeks (range 0.7-79.4 weeks)

Methodology for spleen and symptom assessment

  • Post hoc analyses of spleen volume in the ITT population and Total Symptom Score

  • Only patients who were confirmed responders at the end of cycle 6 were included; patients missing spleen volume assessments at the end of cycle 6 were considered nonresponders

Spleen response (ITT)

30.9%

of patients (N=30/97) experienced ≥35% spleen volume reduction at the end of cycle 6

Symptom response

26.7%

of patients (N=24/90) experienced ≥50% reduction in Total Symptom Score at the end of cycle 6

Includes patients with an evaluable baseline and ≥1 post-baseline assessment of Total Symptom Score.

Adverse reactions with INREBIC® in patients previously treated with ruxolitinib

Hematologic adverse reactions (ITT)

aPresented values are worst-grade values regardless of baseline.

Nonhematologic adverse reactions reported (ITT)

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

aIncludes cystitis.

bPresented values are worst-grade values regardless of baseline.

cOf 96 evaluable patients.

Additional NCCN Guidelines® recommendations for fedratinib3

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) include fedratinib (category 2A) for

  • Patients with intermediate-2 or high-risk myelofibrosis, previously treated with ruxolitinib with no response or loss of response
  • AND platelets ≥50 x 109/L
  • AND who are transplant ineligible

Limitations: JAKARTA2, a phase-2, single-arm, open-label study, was prematurely terminated, which impacts the interpretability of the data. No conclusions regarding the benefits or risks of fedratinib in patients who are resistant or intolerant to ruxolitinib can be established based on this study. These data are not included in the Prescribing Information.

NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Dosing

INREBIC® is started at the full dose (400 mg) in patients with platelets ≥50 x 109/L and is given once daily1

Starting patients on INREBIC®

1

Assess before starting

  • Assess thiamine levels. Do not start INREBIC® in patients with thiamine deficiency; replete thiamine prior to treatment initiation and during treatment if thiamine levels are low

  • Obtain the following blood tests prior to starting treatment with INREBIC®, periodically during treatment, and as clinically indicated: thiamine (vitamin B1) level, complete blood count with platelets, creatinine and BUN, hepatic panel, and amylase and lipase

  • Patients who are on treatment with ruxolitinib before the initiation of INREBIC® must taper and discontinue according to the ruxolitinib prescribing information

  • Avoid use of INREBIC® with strong and moderate CYP3A4 inducers, with dual CYP3A4 and CYP2C19 inhibitors, and in patients with severe hepatic impairment

2

Administer the right starting dose

  • The recommended dosage of INREBIC® is 400 mg taken orally once daily for patients with a baseline platelet count of ≥50 x 109/L

  • Reduce the INREBIC® dose to 200 mg once daily for patients using concomitant strong CYP3A4 inhibitors

  • Reduce the INREBIC® dose to 200 mg once daily for patients with severe renal impairment (creatinine clearance [CLcr] 15 mL/min to 29 mL/min)

  • Interrupt dose until grade 4 neutropenia is resolved to ≤grade 2 or baseline. Restart dose at 100 mg daily below the last given dose

  • Interrupt dose until ≥grade 3 ALT, AST, or bilirubin are ≤grade 1 or baseline. Restart dose at 100 mg daily below the last given dose. Monitor ALT, AST, and bilirubin (total and direct) more frequently following dose reduction. If reoccurrence of a ≥grade 3 elevation, discontinue treatment with INREBIC®

  • Interrupt dose until ≥grade 3 nonhematologic toxicities are resolved to ≤grade 1 or baseline. Restart dose at 100 mg daily below the last given dose

3

Support patients on INREBIC®

  • If encephalopathy is suspected, immediately discontinue treatment with INREBIC® and initiate parenteral thiamine treatment. Monitor until symptoms resolve or improve and thiamine levels normalize

  • The median time to onset of any grade nausea, vomiting, and diarrhea was 1 day, with 75% of cases occurring within 2 weeks of treatment

  • Treat diarrhea with antidiarrheal medications promptly at the first onset of symptoms

  • Consider providing appropriate prophylactic antiemetic therapy (eg, 5-HT3 receptor antagonists) during INREBIC® treatment

  • INREBIC® may be taken with or without food. Administration with a high-fat meal may reduce the incidence of nausea and vomiting

BUN, blood urea nitrogen.

Safety

INREBIC® hematologic safety profile1

Select hematologic events

Selected laboratory abnormalities that have worsened from baseline (≥20%) in patients receiving INREBIC®a

aWith a difference between arms of >10% when compared to placebo in JAKARTA during randomized treatment.

Dose reductions and discontinuations due to hematologic adverse reactions

  • Thrombocytopenia-related dose reductions and discontinuations occurred in 2.1% of patients

  • Anemia-related dose reductions (6%) and discontinuations (1%) occurred with INREBIC®

Median time to onset of lab abnormalities

  • The median time to the first onset of grade 3 anemia was approximately 2 months, with 75% of cases occurring within 3 months

  • The median time to the first onset of grade 3 thrombocytopenia was approximately 1 month, with 75% of cases occurring within 4 months

Transfusions

  • 51% of patients treated with INREBIC® received red blood cell transfusions

  • 3.1% of patients treated with INREBIC® received platelet transfusions

Serious adverse reactions occurred in 21% of patients

  • Serious adverse reactions that occurred in ≥2% of patients included cardiac failure (5%) and anemia (2%). Fatal adverse reactions of cardiogenic shock occurred in 1% of patients receiving INREBIC®

Permanent discontinuation

  • Permanent discontinuation due to an adverse reaction occurred in 14% of patients receiving INREBIC®

Gastrointestinal (GI) and nonhematologic adverse reactions with INREBIC®1

Management of GI adverse reactions

  • Consider providing appropriate prophylactic antiemetic therapy (eg, 5-HT3 receptor antagonists) during INREBIC® treatment

  • Treat diarrhea with antidiarrheal medications promptly at the first onset of symptoms

  • INREBIC® may be taken with or without food. Administration with a high-fat meal may reduce the incidence of nausea and vomiting

Selected adverse reactions reported in patients on INREBIC®

aCommon Terminology Criteria for Adverse Events (CTCAE) version 4.03.

bOnly 1 grade 4 event (anemia).

cIncludes cystitis.

dSelected laboratory abnormalities that have worsened from baseline (≥20%) in patients receiving INREBIC® with a difference between arms of >10% when compared to placebo in JAKARTA during randomized treatment.

MOA

Access and Support

Getting patients started on INREBIC®

INREBIC® is available through the contracted specialty pharmacies or through authorized distributors for in-office dispensing by community physicians, hospitals, institutions, Veterans Affairs, and Department of Defense.

Please download the brochure below to find the listing of contracted specialty pharmacies and authorized distributors.

INREBIC® product information

How supplied

  • INREBIC® 100-mg capsules are supplied in bottles of 120 count each

Storage

  • Store below 86°F (30°C)

Commonly used ICD-10 codes*

  • D47.4 (Osteomyelofibrosis)
  • D75.81 (Myelofibrosis)

*When selecting diagnosis codes, providers should consult a current ICD-10-CM manual and always select the most appropriate diagnosis code(s) with the highest level of detail to describe a patient’s actual condition.

Celgene Patient Support®

A single source for access support

Celgene Patient Support® provides

  • A single Specialist assigned to help patients in your geographic area

  • Assistance with understanding patient insurance coverage for INREBIC®

  • Information about financial assistance for INREBIC®

Financial assistance

There are programs and organizations that may help pay for INREBIC®, depending on a patient’s insurance situation.

Celgene Commercial Co-pay Program
Co-pay responsibility for INREBIC® is reduced to $25 (subject to annual benefit limits) for eligible patients with commercial or private insurance (including healthcare exchanges).

Celgene Patient Assistance Program (PAP)
INREBIC® may be available at no cost for qualified patients who are uninsured or underinsured.

Independent third-party organizations
Patients who are unable to afford their medication (including patients with Medicare, Medicaid, or other government-sponsored insurance) may be able to receive help from independent third-party organizations.§

Other eligibility requirements and restrictions apply. Please see full Terms and Conditions on the Celgene Patient Support® website.

Patients must meet specified financial and insurance eligibility requirements to qualify for assistance. Please see Eligibility Requirements on the Celgene Patient Support® website.

§Financial and medical eligibility requirements vary by organization.

Insurance-related assistance

Our Specialists are available to assist with each of the following steps in the insurance approval process for INREBIC®‖:

  • Benefits investigation

  • Prior authorization assistance

  • Appeals assistance

Celgene cannot provide insurance advice or make insurance decisions.

Celgene provides a facilitation service and will not provide any medical input into a prior authorization or an appeal.

Enrolling in Celgene Patient Support®

Enroll online with Celgene Patient Support

Visit us online at
www.celgenepatientsupport.com

Need additional information?

Call Celgene Patient Support to enroll

Call us at 1-800-931-8691,
Monday–Friday, 8 AM–8 PM ET
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Celgene Patient Support® is a registered trademark of Celgene Corporation. Other trademarks are the property of their respective owners.

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Indication

INREBIC® (fedratinib) is indicated for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF).

IMPORTANT SAFETY INFORMATION

WARNING: ENCEPHALOPATHY INCLUDING WERNICKE’S

Serious and fatal encephalopathy, including Wernicke’s, has occurred in patients treated with INREBIC. Wernicke’s encephalopathy is a neurologic emergency. Assess thiamine levels in all patients prior to starting INREBIC, periodically during treatment, and as clinically indicated. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

WARNINGS AND PRECAUTIONS

Encephalopathy, including Wernicke’s: Serious and fatal encephalopathy, including Wernicke’s encephalopathy, has occurred in INREBIC-treated patients. Serious cases were reported in 1.3% (8/608) of patients treated with INREBIC in clinical trials and 0.16% (1/608) of cases were fatal.

Wernicke’s encephalopathy is a neurologic emergency resulting from thiamine (Vitamin B1) deficiency. Signs and symptoms of Wernicke’s encephalopathy may include ataxia, mental status changes, and ophthalmoplegia (e.g., nystagmus, diplopia). Any change in mental status, confusion, or memory impairment should raise concern for potential encephalopathy, including Wernicke’s, and prompt a full evaluation including a neurologic examination, assessment of thiamine levels, and imaging. Assess thiamine levels in all patients prior to starting INREBIC, periodically during treatment, and as clinically indicated. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

Anemia: New or worsening Grade 3 anemia occurred in 34% of INREBIC-treated patients. The median time to onset of the first Grade 3 anemia was approximately 2 months, with 75% of cases occurring within 3 months. Mean hemoglobin levels reached nadir after 12 to 16 weeks with partial recovery and stabilization after 16 weeks. Red blood cell transfusions were received by 51% of INREBIC-treated patients and permanent discontinuation of INREBIC occurred due to anemia in 1% of patients. Consider dose reduction for patients who become red blood cell transfusion dependent.

Thrombocytopenia: New or worsening Grade 3 thrombocytopenia during the randomized treatment period occurred in 12% of INREBIC-treated patients. The median time to onset of the first Grade 3 thrombocytopenia was approximately 1 month; with 75% of cases occurring within 4 months. Platelet transfusions were received by 3.1% of INREBIC-treated patients. Permanent discontinuation of treatment due to thrombocytopenia and bleeding that required clinical intervention both occurred in 2.1% of INREBIC-treated patients. Obtain a complete blood count (CBC) at baseline, periodically during treatment, and as clinically indicated. For Grade 3 thrombocytopenia with active bleeding or Grade 4 thrombocytopenia, interrupt INREBIC until resolved to less than or equal to Grade 2 or baseline. Restart dose at 100 mg daily below the last given dose and monitor platelets as clinically indicated.

Gastrointestinal Toxicity: Gastrointestinal toxicities are the most frequent adverse reactions in INREBIC-treated patients. During the randomized treatment period, diarrhea occurred in 66% of patients, nausea in 62% of patients, and vomiting in 39% of patients. Grade 3 diarrhea 5% and vomiting 3.1% occurred. The median time to onset of any grade nausea, vomiting, and diarrhea was 1 day, with 75% of cases occurring within 2 weeks of treatment. Consider providing appropriate prophylactic anti-emetic therapy (e.g., 5-HT3 receptor antagonists) during INREBIC treatment. Treat diarrhea with anti-diarrheal medications promptly at the first onset of symptoms. Grade 3 or higher nausea, vomiting, or diarrhea not responsive to supportive measures within 48 hours, interrupt INREBIC until resolved to Grade 1 or less or baseline. Restart dose at 100 mg daily below the last given dose. Monitor thiamine levels and replete as needed.

Hepatic Toxicity: Elevations of ALT and AST (all grades) during the randomized treatment period occurred in 43% and 40%, respectively, with Grade 3 or 4 in 1% and 0%, respectively, of INREBIC-treated patients. The median time to onset of any grade transaminase elevation was approximately 1 month, with 75% of cases occurring within 3 months. Monitor hepatic function at baseline, periodically during treatment, and as clinically indicated. For Grade 3 or higher ALT and/or AST elevations (greater than 5 × ULN), interrupt INREBIC dose until resolved to Grade 1 or less or to baseline. Restart dose at 100 mg daily below the last given dose. If re-occurrence of a Grade 3 or higher elevation of ALT/AST, discontinue treatment with INREBIC.

Amylase and Lipase Elevation: Grade 3 or higher amylase 2% and/or lipase 10% elevations developed in INREBIC-treated patients. The median time to onset of any grade amylase or lipase elevation was 15 days, with 75% of cases occurring within 1 month of starting treatment. One patient developed pancreatitis in the fedratinib clinical development program (n=608) and pancreatitis resolved with treatment discontinuation. Monitor amylase and lipase at baseline, periodically during treatment, and as clinically indicated. For Grade 3 or higher amylase and/or lipase elevations, interrupt INREBIC until resolved to Grade 1 or less or to baseline. Restart dose at 100 mg daily below the last given dose.

ADVERSE REACTIONS:

The most common adverse reactions for INREBIC treated vs. placebo were diarrhea (66% vs. 16%), nausea (62% vs. 15%), anemia (40% vs. 14%), and vomiting (39% vs. 5%). Dosage interruptions due to an adverse reaction during the randomized treatment period occurred in 21% of patients who received INREBIC. Adverse reactions requiring dosage interruption in >3% of patients who received INREBIC included diarrhea and nausea. Dosage reductions due to an adverse reaction during the randomized treatment period occurred in 19% of patients who received INREBIC. Adverse reactions requiring dosage reduction in >2% of patients who received INREBIC included anemia (6%), diarrhea (3%), vomiting (3%), and thrombocytopenia (2%).

DRUG INTERACTIONS:

Coadministration of INREBIC with a strong CYP3A4 inhibitor increases fedratinib exposure. Increased exposure may increase the risk of adverse reactions. Consider alternative therapies that do not strongly inhibit CYP3A4 activity. Alternatively, reduce the dose of INREBIC when administering with a strong CYP3A4 inhibitor. Avoid INREBIC with strong and moderate CYP3A4 inducers. Avoid INREBIC with dual CYP3A4 and CYP2C19 inhibitor. Coadministration of INREBIC with drugs that are CYP3A4 substrates, CYP2C19 substrates, or CYP2D6 substrates increases the concentrations of these drugs, which may increase the risk of adverse reactions of these drugs. Monitor for adverse reactions and adjust the dose of drugs that are CYP3A4, CYP2C19, or CYP2D6 substrates as necessary when coadministered with INREBIC.

PREGNANCY/LACTATION: Consider the benefits and risks of INREBIC for the mother and possible risks to the fetus when prescribing INREBIC to a pregnant woman. Due to the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with INREBIC, and for at least 1 month after the last dose.

RENAL IMPAIRMENT: Reduce INREBIC dose when administered to patients with severe renal impairment. No modification of the starting dose is recommended for patients with mild to moderate renal impairment. Due to potential increase of exposure, patients with preexisting moderate renal impairment require more intensive safety monitoring, and if necessary, dose modifications based on adverse reactions.

HEPATIC IMPAIRMENT: Avoid use of INREBIC in patients with severe hepatic impairment.

Please click here for full Prescribing Information, including Boxed WARNING.

REFERENCES

1. INREBIC® [package insert]. Summit, NJ: Celgene Corporation; 2019. 2. Data on file. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Myeloproliferative Neoplasms V.3.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed September 4, 2019. To view the most recent and complete version of the guideline, go online to NCCN.org.



Information for Vermont Prescribers of Prescription Drugs INREBIC® (fedratinib) capsules