DRUG INTERACTIONS-(summary)

 Strong CYP3A4 Inhibitors: Reduce INREBIC dose as recommended 

Strong and Moderate CYP3A4 Inducers: Avoid use of INREBIC Dual CYP3A4 and CYP2C19 Inhibitor: Avoid use of INREBIC

DRUG INTERACTIONS (details)

1 Effect of Other Drugs on INREBIC Strong CYP3A4 Inhibitors-             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.

 Strong and Moderate CYP3A4 Inducers -

Avoid INREBIC with strong and moderate CYP3A4 inducers. The effect of concomitant administration of a strong or moderate CYP3A4 inducer with INREBIC has not been studied 

Dual CYP3A4 and CYP2C19 Inhibitors Avoid INREBIC with dual CYP3A4 and CYP2C19 inhibitor.

The effect of concomitant administration of a dual CYP3A4 and CYP2C19 inhibitor with INREBIC has not been studied

2. Effect of INREBIC on Other Drugs CYP3A4, CYP2C19, or CYP2D6 Substrate

Drugs 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.

 BRIEF SUMMARY

INREBIC- (Aug 2019)

indn-    To treat adult patients with intermediate  or high risk primary or secondary  myelofibrosis

Comp-     Capsules: 100 mg    Recommended Dosage: 400 mg orally once daily with or without food for patients with a baseline platelet count of greater than or equal to 50 x 10

ADR-

CI-

Pat  Inform-

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 U.S. FDA APPROVED  DRUGS DURING 2019

Sr.No-  22.

ADVERSE REACTIONS-

 The most common adverse reactions (=20%) are diarrhea, nausea, anemia, and vomiting

WARNINGS AND PRECAUTIONS-

 Anemia and Thrombocytopenia: Manage by dose reduction, interruption, or transfusion (

 Gastrointestinal Toxicity: Manage by dose reduction or interruption if patient develops severe diarrhea, nausea, or vomiting. Prophylaxis with anti-emetics and treatment with anti-diarrhea medications are recommended

 Hepatic Toxicity: Manage by dose reduction or interruption

 Amylase and Lipase Elevation: Manage by dose reduction or interruption

PATIENT COUNSELING INFORMATION -

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Discuss the following with patients prior to and during treatment with INREBIC. Encephalopathy, including Wernicke’s

Advise patients that serious and fatal encephalopathy, including Wernicke’s, has occurred in patients taking INREBIC. Wernicke’s encephalopathy is a neurological emergency resulting from acute thiamine (Vitamin B1) deficiency.

Advise patients of the need to monitor thiamine levels [see Dosage and Administration (2.1, 2.2, 2.6), and Warnings and Precautions (5.1)].

Advise patients to seek emergency medical attention for any change in mental status such as confusion, drowsiness or memory impairment, cerebellar abnormalities such as ataxia, and ophthalmic abnormalities such as diplopia and nystagmus.

Advise patients to contact their healthcare provider right away if they experience nausea, vomiting, diarrhea, and weight loss unresponsive to treatment resulting in malnutrition and lower thiamine levels, which may lead to Wernicke’s encephalopathy [see Boxed Warning and Warnings and Precautions (5.1)]. Anemia and Thrombocytopenia

Advise patients that INREBIC is associated with anemia and thrombocytopenia, and of the need to monitor complete blood counts before and during treatment [see Warnings and Precautions (5.2)].

Gastrointestinal Toxicity Advise patients to contact their healthcare provider if they experience intractable diarrhea, nausea, or vomiting.

Prescribers should advise patients of the potential complications of severe diarrhea, nausea, or vomiting [see Warnings and Precautions (5.3)].

Hepatic Toxicity Advise patients that INREBIC may increase liver enzymes and of the need to monitor liver enzyme levels [see Warnings and Precautions (5.4)].

Amylase and Lipase Elevation Advise patients that INREBIC may increase amylase and lipase and of the need to monitor amylase and lipase [see Warnings and Precautions (5.5)].

Lactation Advise patients not to breastfeed during treatment with INREBIC and for at least 1 month after the final dose [see Use in Specific Populations (8.2)]. Reference ID: 4478261

Dosing and Storage Instructions ? Instruct patients that if they miss a dose of INREBIC, skip the dose and take it the next day and return to normal schedule [see Dosage and Administration (2.1)]. Warn patients not to take 2 doses to make up for the missed dose.

Manufactured for and marketed by: Celgene Corporation Summit, NJ 07901 INREBIC® is a registered trademark of Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation. Pat. www.celgene.com/therapies © 2018 - 2019 Impact Biomedicines, Inc. All Rights Reserved. INRPI.001/MG.001 08/19

CLINICAL PHARMACOLOGY

1. Mechanism of Action

Fedratinib is an oral kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3).

Fedratinib is a JAK2-selective inhibitor with higher inhibitory activity for JAK2 over family members JAK1, JAK3 and TYK2.

Abnormal activation of JAK2 is associated with myeloproliferative neoplasms (MPNs), including myelofibrosis and polycythemia vera. In cell models expressing mutationally active JAK2V617F or FLT3ITD, fedratinib reduced phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibited cell proliferation, and induced apoptotic cell death. In mouse models of JAK2V617F-driven myeloproliferative disease, fedratinib blocked phosphorylation of STAT3/5, and improved survival, white blood cell counts, hematocrit, splenomegaly, and fibrosis.

2. Pharmacodynamics-

Fedratinib inhibited cytokine-induced STAT3 phosphorylation in whole blood from patients with myelofibrosis.

The inhibition of STAT3 phosphorylation was maximal approximately 2 hours after the first dose, with values returning to near baseline at 24 hours.

After daily administration of fedratinib, levels of inhibition at steady state PK were similar to the maximal inhibition reached after the first dose of 300 (0.75 times the recommended dose), 400 or 500 mg (1.25 times the recommended dose) of fedratinib.

Cardiac Electrophysiology-

 The potential for QTc prolongation with fedratinib was evaluated in 31 patients with solid tumors. No large mean increase in the QTc interval (>20 ms) was detected with daily dosing of fedratinib 500 mg (1.25 times the recommended dose) for 14 days.

3 Pharmacokinetics-

INREBIC at 300 mg to 500 mg once daily (0.75 to 1.25 times the recommended dose) results in a dose proportional increase in geometric mean fedratinib peak concentrations (Cmax) and the area under the plasma concentration time curve over the dosing interval (AUCtau).

The mean steady state levels are achieved within 15 days of daily dosing. The mean accumulation ratio ranged between 3- to 4-fold. At the dose of 400 mg once daily, the geometric mean (coefficient of variation, %CV) fedratinib Cmax is 1804 Reference ID: 4478261 ng/mL (49%) and AUCtau is 26870 ng.hr/mL (43%) in patients with myelofibrosis

 Absorption-

Following 400 mg once daily, fedratinib median time to peak concentrations (Tmax) at steady-state is 3 hours (range: 2 to 4 hours.

 Effect of Food-

 A low-fat, low-calorie (total 162 calories: 6% from fat, 78% from carbohydrate and 16% from protein) or a high-fat, high-calorie (total 815 calories: 52% from fat, 33% from carbohydrate and 15% from protein) meal increased area under the curve over time to infinity (AUCinf) up to 24% and Cmax up to 14% of a single 500 mg dose of fedratinib.

Distribution-

The apparent volume of distribution of fedratinib at steady-state is 1770 L in patients with myelofibrosis at 400 mg once daily dose. Fedratinib is 92% or greater bound to human plasma proteins.

Elimination

Fedratinib pharmacokinetics is characterized by a biphasic disposition with an effective half-life of 41 hours, a terminal half-life of approximately 114 hours, and apparent clearance (CL/F) (%CV) of 13 L/hr (51%) in patients with myelofibrosis.

Metabolism-

Fedratinib is metabolized by CYP3A4, CYP2C19, and flavin-containing monooxygenase 3 (FMO3). Fedratinib accounts for approximately 80% of total circulating drug in plasma after oral administration.

Excretion-

Following a single oral dose of radiolabeled fedratinib, 77% (23% unchanged) of the administered dose was excreted in feces and 5% (3% unchanged) was eliminated in urine.

Specific Populations-

Age (20 years to 95 years), race (White, Asians), sex, body weight (40 kg to 135 kg), mild [total bilirubin =upper limit of normal (ULN) and AST >ULN or total bilirubin 1 to 1.5 times ULN and any AST] or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment, and mild (CLcr 60 mL/min to 89 mL/min by C-G) renal impairment did not have clinically meaningful effects on the pharmacokinetics of fedratinib.

The effect of severe (total bilirubin >3 times ULN and any AST) hepatic impairment on fedratinib pharmacokinetics is unknown.

Patients with Renal Impairment-

Following a single 300 mg dose of INREBIC, the AUCinf of fedratinib increased by 1.5-fold in subjects with moderate (CLcr 30 mL/min to 59 mL/min by C-G) renal impairment and 1.9-fold in subjects with severe (CLcr 15 mL/min to 29 mL/min by C-G) renal impairment, compared to that in subjects with normal renal function (CLcr =90 mL/min by C-G)

Drug Interaction Studies -                                                                                      Clinical Studies and Model-Informed Approaches

Effect of Strong and Moderate CYP3A4 Inhibitors Coadministration of ketoconazole (strong CYP3A4 inhibitor: 200 mg twice daily) with a single dose of INREBIC (300 mg) increased fedratinib AUCinf by 3-fold [see Dosage and Administration (2.3) and Drug Interactions (7.1)].

Based on modeling and simulation, coadministration of a strong CYP3A4 inhibitor such as ketoconazole (400 mg once daily) with INREBIC 400 mg once daily is predicted to increase fedratinib AUC at steady state by 2- fold [see Dosage and Administration (2.3) and Drug Interactions (7.1)].

Based on modeling and simulation, coadministration of moderate CYP3A4 inhibitors, erythromycin (500 mg three times daily) or diltiazem (120 mg twice daily), with INREBIC 400 mg once daily is predicted to increase fedratinib AUC at steady state by 1.2-, and 1.1-fold, respectively.

Effect of Dual CYP3A4 and CYP2C19 Inhibitor The effect of concomitant administration with a dual CYP3A4 and CYP2C19 inhibitor on fedratinib pharmacokinetics is not known [see Drug Interactions (7.1)]

Effect of Strong and Moderate CYP3A4 Inducers The effect of concomitant administration with a strong or moderate CYP3A4 inducer on fedratinib pharmacokinetics is not known [see Drug Interactions (7.1)].

Effect of Gastric Acid Reducing Agents Coadministration of pantoprazole (proton pump inhibitor: 40 mg once daily) with a single dose of INREBIC (500 mg) increased fedratinib AUCinf by 1.2-fold.

Effect of Fedratinib on Drugs that are CYP3A, CYP2C19, or CYP2D6 Substrates Coadministration of a single dose of midazolam (CYP3A substrate: 2 mg), omeprazole (CYP2C19 substrate: 20 mg), and metoprolol (CYP2D6 substrate: 100 mg) increased midazolam, omeprazole, or metoprolol AUCinf by 4-, 3-, and 2-fold, respectively [see Drug Interactions (7.2)].

In Vitro Studies Fedratinib as a Substrate for Transporters: Fedratinib is a substrate of P-glycoprotein (P-gp) but not breast cancer resistance protein (BCRP), BSEP, multidrug resistance protein (MRP), MRP2, and organic anion transporting polypeptide (OATP)1B1 and OATP1B3

Effect of Fedratinib on Transporter Substrates Fedratinib inhibits P-gp, BCRP, OATP1B1, OATP1B3, organic cation transporter (OCT)2, multidrug and toxin extrusion (MATE) protein 1, and MATE-2K, but not BSEP, MRP2, and organic anion transporter (OAT)1 and OAT3 in vitro. Reference ID: 4478261

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Fedratinib was not carcinog

USE IN SPECIFIC POPULATIONS-

1. Pregnancy Risk Summary-

There are no available data on INREBIC use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of fedratinib to pregnant rats during organogenesis at doses considerably lower than the recommended human daily dose of 400 mg/day resulted in adverse developmental outcomes (see Data).

Consider the benefits and risks of INREBIC for the mother and possible risks to the fetus when prescribing INREBIC to a pregnant woman.

The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

2. Lactation Risk Summary -

There are no data on the presence of fedratinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production.

Because of 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.

3.Pediatric Use -

The safety and effectiveness of INREBIC in pediatric patients have not been established.

5. Geriatric Use -

Of the total number of patients with myelofibrosis who received an INREBIC dose of 400 mg in the clinical studies, 47.3% were greater than 65 years of age and 12.3% were greater than 75 years of age.

No overall differences in safety or effectiveness of INREBIC were observed between these patients and younger patients

6. Renal Impairment -

Reduce INREBIC dose when administered to patients with severe renal impairment (CLcr 15 mL/min to 29 mL/min by Cockcroft-Gault)..

No modification of the starting dose is recommended for patients with mild to moderate renal impairment (CLcr 30 mL/min to 89 mL/min by Cockcroft-Gault).

Due to potential increase of exposure, patients with pre-existing moderate renal impairment require more intensive safety monitoring, and if necessary, dose modifications based on adverse reactions.

7. Hepatic Impairment-

 INREBIC pharmacokinetics has not been evaluated in patients with severe hepatic impairment (total bilirubin > 3 times ULN and any AST). Avoid use of INREBIC in patients with severe hepatic impairment