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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US healthcare professionals.

Study Design1,2

Double-blind, randomized, placebo-controlled, phase-3 study (N=289) in patients with intermediate-2 or high-risk primary or secondary myelofibrosis

IPSS, International Prognostic Scoring System; qd, once daily.

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

Efficacy1,2

Spleen reduction in the intent-to-treat (ITT) population with INREBIC®

Percent of Patients with SVR ≥35% At the end of cycle 6 with a scan 4 weeks later

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

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

Percent Change in Spleen Volume at the end of cycle 6 For Each Patient

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

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

Symptom reduction with INREBIC®

Percent of Patients with ≥50% Reduction in TSS at the end of cycle 6

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

Percent Change in TSS At the End of Cycle 6 for each patient

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

aSubjects 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 ribs on left side, and bone or muscle pain.

INREBIC® in patients previously treated with ruxolitinib

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.

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 of INREBIC® during enrollment in study was 24 weeks (range 0.7-79.4 weeks)

Spleen and symptom response of INREBIC®

The original JAKARTA2 study analysis included the per-protocol population and used last-observation-carried-forward (LOCF) analysis method for spleen volume. The LOCF method allowed for the last spleen volume assessment to be “carried forward” (imputed) for patients missing end-of-cycle-6 assessments. The following reanalysis included the all-enrolled population (ITT) and the LOCF method was not employed. As such, missing data were not imputed for assessments of spleen volume, and patients missing 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

Adverse reactions with INREBIC® in patients previously treated with ruxolitinib

Hematologic Adverse Reactions (ITT)

hematologic adverse reactions (ITT)

aPresented values are worse-grade values regardless of baseline.

Nonhematologic ADVERSE REACTIONS REPORTED (ITT)

nonhematologic adverse reactions reported (ITT)

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

aIncludes cystitis.

bPresented values are worse-grade values regardless of baseline.

cOf 96 evaluable patients.

Dosing1

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 in patients with severe renal impairment (creatinine clearance [CLcr] 15 mL/min to 29 mL/min)

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.

Safety1

Hematologic adverse reactions for INREBIC®

  • 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 of treatment due to anemia occurred in 1% of patients receiving INREBIC®

  • Permanent discontinuation of treatment due to thrombocytopenia occurred in 2.1% of patients receiving INREBIC®

Selected Laboratory Abnormalities that have worsened from baseline (≥20%) in Patients Receiving Inrebic®a

selected laboratory abnormalities that have worsened from baseline (greater than or equal to 20 percent) in patients receiving INREBIC

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

Most common adverse reactions with INREBIC®

Management of gastrointestinal 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®

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.

Encephalopathy1

Cases of encephalopathy, including Wernicke's encephalopathy (WE), with INREBIC®

Overview of encephalopathy, including WE, in the INREBIC® clinical development program

  • 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

Mechanism of Action1

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

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

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

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

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

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.

Learn More about Financial Assistance

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/precertification 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.

Learn More about Insurance-Related Assistance

Enrolling in Celgene Patient Support®

There are 3 simple ways to enroll in Celgene Patient Support®

Call Celgene Patient Support to enroll

Call us at 1-800-931-8691,
Monday–Friday, 8 AM–8 PM ET
(translation services available).

Email Celgene Patient Support to enroll

E-mail a completed enrollment form to
patientsupport@celgene.com
or fax 1-800-822-2496.

Register for Updates

  • Register to receive information and updates about INREBIC®

    *Required field

  • Celgene values your privacy. Celgene, its affiliates, and its agents will not sell or rent your personal information. By providing your information, you acknowledge that you have read and agree to Celgene's Privacy Policy.

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% 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 patient 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.



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