This promotional presentation  is being sponsored by Bristol- Myers Squibb Company. The speaker is presenting on behalf of Bristol-Myers Squib Company.

Hi, my name is Dr Ruben Mesa. I am the director of the Mayo Cancer Center at UT Health San Antonio MD Anderson here in San Antonio, Texas. I have cared for myelofibrosis patients for almost 30 years.

In this video, I am going to review the trial data related to INREBIC, also known as fedratinib.

INREBIC is indicated for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or postessential thrombocythemia) myelofibrosis. This indication statement is broad. Therefore, INREBIC could be an option for patients who are naïve to JAK inhibitors, or for patients previously treated with ruxolitinib.

INREBIC contains a Boxed Warning for Encephalopathy, including Wernicke’s. Serious encephalopathy, including Wernicke’s, occurred in 8 out of 608 patients in the development program. One patient had a fatal outcome.

Wernicke’s is a neurologic emergency resulting from thiamine (Vitamin B) deficiency. As such, it is important to assess thiamine levels in all patients prior to starting INREBIC and periodically during treatment as clinically indicated. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation. Signs and symptoms of encephalopathy, including Wernicke’s, may include the following: 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.

If you suspect encephalopathy while on treatment with INREBIC, discontinue immediately and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

In terms of dosing, INREBIC is started at the full dose (400 mg) in patients with platelets ≥50 x 109/L and is given once daily. Obtain these 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 blood urea nitrogen
• Hepatic panel
• Amylase and lipase

In cases of concomitant use of strong CYP3A4 inhibitors and patients who have severe renal impairment, start at 200mg. Importantly, you should avoid use of INREBIC with strong and moderate CYP3A4 inducers, dual CYP3A4 and CYP2C19 inhibitors, and with severe hepatic impairment. When giving INREBIC, it may be taken with or without food, and taking it with a high-fat meal may reduce incidence of nausea and vomiting.

If you are going to use INREBIC for patients who are on ruxolitinib, make sure you discontinue ruxolitinib before initiation of INREBIC, and taper according to the ruxolitinib prescribing information.

The pivotal study, JAKARTA, included JAK inhibitor naïve patients and supported the approval of INREBIC. The JAKARTA study enrolled patients with intermediate-2 or high-risk primary and secondary myelofibrosis with splenomegaly.

Patients were randomized equally 1:1:1 to 500 mg and 400 mg of INREBIC vs placebo and patients continued to receive INREBIC as long as they were benefitting. Crossover after the randomization period was allowed.

As I mentioned previously, the recommended dose in the USPI is 400mg. As such I will be presenting data from this arm moving forward.

In the intent-to-treat population, 37% of patients achieved the primary endpoint of spleen volume reduction ≥35% at the end of cycle 6, with a scan 4 weeks later. This is compared to 1% of patients who did so in the placebo group. Based on Kaplan-Meier estimates, the median duration of spleen response was 18.2 months for the INREBIC 400mg group.

I will now turn my attention to the secondary endpoint of the study and present symptom reduction with INREBIC.

In the symptom evaluable population, 40% experienced ≥50% reduction in Total Symptom Score at the end of cycle 6 vs 9% receiving placebo.

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

– Patients with higher-risk (intermediate-2 or high risk) myelofibrosis

– AND platelets ≥50 x 109/L

– AND who are transplant ineligible

In addition to the pivotal study, there was a single-arm, phase 2 study that was done in patients who were previously treated with ruxolitinib. The JAKARTA2 study was prematurely terminated, which therefore impacts the interpretability of the data. We cannot draw any conclusions regarding the benefit or risk of INREBIC in this patient population and these data are not in the prescribing information. However, I will share some information from this study.

The JAKARTA2 study included 97 patients with primary or secondary myelofibrosis who were 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 the study was 10.7 months. Median exposure to INREBIC during enrollment in the study was 24 weeks (range 0.7 – 79.4 weeks).

In the post hoc analysis, only patients in the ITT population 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.

When employing this methodology…

…30.9% of the patients experienced ≥35% spleen volume reduction and 26.7% of patients experienced ≥50% reduction in Total Symptom Score at the end of cycle 6.

In patients previously treated with ruxolitinib, hematologic adverse events were observed, including anemia (99.0%), thrombocytopenia (70.1%), and neutropenia (24.0%).

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

– Patients with higher risk (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

This guideline has its 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.

It is important to assess the patient and the available data before making a decision on what is right for your patient.

Presented onscreen are the nonhematologic adverse reactions that were observed in patients previously treated with ruxolitinib in the JAKARTA2 trial. The most frequently reported adverse reactions included increased creatinine (74.2%), diarrhea (61.9%), nausea (55.7%), and increased AST and ALT (47.4% and 45.4%, respectively).

Now let’s get into specifics of the adverse reactions seen in the phase 3 JAKARTA trial. INREBIC was associated with hematologic laboratory abnormalities, such as anemia (74%), thrombocytopenia (47%), and neutropenia (23% of patients).

Permanent discontinuation of treatment due to anemia occurred in 1% of patients receiving INREBIC. Permanent discontinuation of treatment due to thrombocytopenia and bleeding that required clinical intervention occurred in 2.1% of patients receiving 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 cardiogenic shock occurred in 1% of patients receiving INREBIC.

Permanent discontinuation due to an adverse reaction occurred in 14% of patients receiving INREBIC. The median time to onset of the first grade 3 anemia was approximately 2 months, with 75% of cases occurring within 3 months. The median time to onset of the first grade 3 thrombocytopenia was approximately 1 month, with 75% of cases occurring within 4 months.

Red blood cell transfusions were received by 51% of INREBIC-treated patients. Platelet transfusions were received by 3.1% of INREBIC treated patients.

Shown on screen are the most common adverse reactions reported in patients taking INREBIC. Note that these are during the randomized treatment period. The most frequently reported adverse reactions included diarrhea (66%), nausea (62%), vomiting (39%), and anemia (40%).

This trial provided key efficacy and safety data for INREBIC.

INDICATION

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

IMPORTANT SAFETY INFORMATION

INREBIC contains a Boxed Warning for Encephalopathy, including Wernicke’s.

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.

2010-US-2100066 06/21

This promotional presentation is being sponsored by Bristol- Myers Squibb Company. The speaker is presenting on behalf of Bristol-Myers Squibb Company.

Hi, my name is Dr Ruben Mesa. I am the director of the Mays Cancer Center at UT Health San Antonio MD Anderson here in San Antonio, Texas.

I have cared for MF patients for almost 30 years. In this video I will discuss important considerations when starting your patients on INREBIC, also known as fedratinib.

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

This indication statement is broad. Therefore, INREBIC could be an option for patients who are naïve to JAK inhibitors, or for patients previously treated with ruxolitinib.

INREBIC contains a Boxed Warning for Encephalopathy, including Wernicke’s. Serious encephalopathy, including Wernicke’s, occurred in 8 out of 608 patients in the development program. One patient had a fatal outcome.

Wernicke’s is a neurologic emergency resulting from thiamine (Vitamin B) deficiency. As such, it is important to assess thiamine levels in all patients prior to starting INREBIC and periodically during treatment as clinically indicated. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation.

Signs and symptoms of encephalopathy, including Wernicke’s, may include the following: 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. If you suspect encephalopathy while on treatment with INREBIC, discontinue immediately and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

The process of starting patients on INREBIC therapy can be outlined in 3 general phases. 1. Assess the patient before starting INREBIC. 2. Administer the right starting dose for your patient. And, 3. Support the patient on INREBIC therapy throughout use. Let’s talk through these together.

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.

Obtain these 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 blood urea nitrogen
• Hepatic panel
• Amylase and lipase

If you are going to use INREBIC for patients who are on ruxolitinib, make sure you discontinue ruxolitinib before initiation of INREBIC, and taper according to the ruxolitinib prescribing information.

INREBIC is started at the full dose, 400 mg, in patients with a baseline platelet count ≥50 × 109/L. The dose is given once daily.

In cases of concomitant use of strong CYP3A4 inhibitors and in patients who have severe renal impairment, start at 200mg.

You should avoid use of INREBIC with strong and moderate CYP3A4 inducers, dual CYP3A4 and CYP2C19 inhibitors, and with severe hepatic impairment. Interrupt dose until Grade 4 Neutropenia is resolved to Grade 2 or lower or baseline. Restart dose at 100 mg daily below the last given dose.

Interrupt dose until Grade 3 or higher ALT, AST, or Bilirubin are Grade 1 or lower 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 or higher elevation, discontinue treatment with INREBIC. Interrupt dose until Grade 3 or higher Nonhematologic Toxicities are resolved to Grade 1 or lower or baseline. Restart dose at 100 mg daily below the last given dose.

If Wernicke’s 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 such as 5-HT3 receptor antagonists during INREBIC treatment.

When giving INREBIC, it may be taken with or without food, and taking it with a high-fat meal may help to reduce incidence of nausea and vomiting.

With this guidance on assessment and monitoring, dosage and administration, and supporting your patients, you can guide patients through the process of starting INREBIC therapy.

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

INREBIC contains a Boxed Warning for Encephalopathy, including Wernicke’s.

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.

US-INR-19-0178 01/20