DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Confirm the presence of an FGFR2 fusion or rearrangement prior to initiation of treatment with PEMAZYRE. (2.1)Recommended dosage is 13.5 mg orally once daily for 14 consecutive days followed by days off therapy in 21-day cycles. Continue treatment until disease progression or unacceptable toxicity occurs. (2.2)Swallow tablet whole, with or without food. (2.2)Severe renal impairment: the recommended dosage of PEMAZYRE is mg orally once daily for 14 consecutive days followed by days off therapy in 21-day cycles. (2.5, 8.6, 12.3)Severe Hepatic Impairment: the recommended dosage of PEMAZYRE is mg orally once daily for 14 consecutive days followed by days off therapy in 21-day cycles. (2.6, 8.7, 12.3). Confirm the presence of an FGFR2 fusion or rearrangement prior to initiation of treatment with PEMAZYRE. (2.1). Recommended dosage is 13.5 mg orally once daily for 14 consecutive days followed by days off therapy in 21-day cycles. Continue treatment until disease progression or unacceptable toxicity occurs. (2.2). Swallow tablet whole, with or without food. (2.2). Severe renal impairment: the recommended dosage of PEMAZYRE is mg orally once daily for 14 consecutive days followed by days off therapy in 21-day cycles. (2.5, 8.6, 12.3). Severe Hepatic Impairment: the recommended dosage of PEMAZYRE is mg orally once daily for 14 consecutive days followed by days off therapy in 21-day cycles. (2.6, 8.7, 12.3). 2.1 Patient Selection. Select patients for the treatment of locally advanced or metastatic cholangiocarcinoma with PEMAZYRE based on the presence of an FGFR2 fusion or rearrangement as detected by an FDA-approved test [see Clinical Studies (14.1 )]. Information on FDA-approved test(s) for the detection of an FGFR2 fusion or rearrangement in cholangiocarcinoma is available at http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage. The recommended dosage of PEMAZYRE is 13.5 mg orally once daily for 14 consecutive days followed by days off therapy, in 21-day cycles. Continue treatment until disease progression or unacceptable toxicity occurs.Take PEMAZYRE with or without food at approximately the same time every day [see Clinical Pharmacology 12.3 )].Swallow tablets whole. Do not crush, chew, split, or dissolve tablets.If the patient misses dose of PEMAZYRE by or more hours or if vomiting occurs, resume dosing with the next scheduled dose.. 2.3 DosageModification for Adverse Reactions. The recommended dose reductions for adverse reactions are provided in Table 1.Table 1: Recommended Dose Reductions for PEMAZYRE for Adverse Reactions Dose Reduction Recommended Dosage First mg once daily for first 14 days of each 21-day cycle SecondPermanently discontinue PEMAZYRE if unable to tolerate 4.5 mg once daily. 4.5 mg once daily for first 14 days of each 21-day cycleThe recommended dosage modifications for adverse reactions are provided in Table 2.Table 2: Recommended Dosage Modifications for PEMAZYRE Adverse ReactionsAdverse ReactionSeveritySeverity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03. PEMAZYRE Dosage ModificationRetinal Pigment Epithelial Detachment (RPED) [see Warnings and Precautions 5.1)] RPEDIf asymptomatic and stable on serial examination, continue PEMAZYRE.If symptomatic or worsening on serial examination, withhold PEMAZYRE.If asymptomatic and improved on subsequent examination, resume PEMAZYRE at lower doseIf symptoms persist or examination does not improve, consider permanent discontinuation of PEMAZYRE, based on clinical status. Hyperphosphatemia [see Warnings and Precautions 5.2 )] Serum phosphate 7 mg/dL- <=10 mg/dLInitiate phosphate lowering therapy and monitor serum phosphate weekly.Withhold PEMAZYRE if levels are not 7 mg/dL within weeks of starting phosphate lowering therapy.Resume PEMAZYRE at the same dose when phosphate levels are 7 mg/dL for first occurrence; resume at lower dose level for subsequent recurrences. Serum phosphate >10 mg/dL Initiate phosphate lowering therapy and monitor serum phosphate weekly.Withhold PEMAZYRE if levels are not <= 10 mg/dL within week after starting phosphate lowering therapy.Resume PEMAZYRE at the next lower dose level when phosphate levels are 7 mg/dL.Permanently discontinue PEMAZYRE for recurrence of serum phosphate 10mg/dL following dose reductions.Other Adverse ReactionsGrade 3Withhold PEMAZYRE until resolves to Grade or baseline.Resume PEMAZYRE at next lower dose if resolves within weeks. Permanently discontinue PEMAZYRE if does not resolve within weeks.Permanently discontinue PEMAZYRE for recurrent Grade after dose reductions.Grade 4Permanently discontinue PEMAZYRE.. If asymptomatic and stable on serial examination, continue PEMAZYRE.. If symptomatic or worsening on serial examination, withhold PEMAZYRE.If asymptomatic and improved on subsequent examination, resume PEMAZYRE at lower doseIf symptoms persist or examination does not improve, consider permanent discontinuation of PEMAZYRE, based on clinical status. If asymptomatic and improved on subsequent examination, resume PEMAZYRE at lower dose. If symptoms persist or examination does not improve, consider permanent discontinuation of PEMAZYRE, based on clinical status. Initiate phosphate lowering therapy and monitor serum phosphate weekly.. Withhold PEMAZYRE if levels are not 7 mg/dL within weeks of starting phosphate lowering therapy.. Resume PEMAZYRE at the same dose when phosphate levels are 7 mg/dL for first occurrence; resume at lower dose level for subsequent recurrences. Initiate phosphate lowering therapy and monitor serum phosphate weekly.. Withhold PEMAZYRE if levels are not <= 10 mg/dL within week after starting phosphate lowering therapy.. Resume PEMAZYRE at the next lower dose level when phosphate levels are 7 mg/dL.. Permanently discontinue PEMAZYRE for recurrence of serum phosphate 10mg/dL following dose reductions.. Withhold PEMAZYRE until resolves to Grade or baseline.. Resume PEMAZYRE at next lower dose if resolves within weeks. Permanently discontinue PEMAZYRE if does not resolve within weeks.. Permanently discontinue PEMAZYRE for recurrent Grade after dose reductions.. Permanently discontinue PEMAZYRE.. 2.4 Dosage Modification for Concomitant Use with Strong or Moderate CYP3A Inhibitors. Avoid concomitant use of strong and moderate CYP3A inhibitors with PEMAZYRE. If concomitant use with strong or moderate CYP3A inhibitor cannot be avoided:Reduce PEMAZYRE dosage from 13.5 mg to mg.Reduce PEMAZYRE dosage from mg to 4.5 mg. If concomitant use of strong or moderate CYP3A inhibitor is discontinued, increase the PEMAZYRE dosage (after plasma half-lives of the CYP3A inhibitor) to the dosage that was used before starting the strong or moderate inhibitor [see Clinical Pharmacology 12.3 )].. Reduce PEMAZYRE dosage from 13.5 mg to mg.. Reduce PEMAZYRE dosage from mg to 4.5 mg. 2.5 Recommended Dosage for Severe Renal Impairment. The recommended dosage of PEMAZYRE for patients with severe renal impairment (eGFR estimated by MDRD 15 to 29 mL/min/1.73 m2) is mg orally once daily for 14 consecutive days followed by days off therapy, in 21-day cycles [see Renal Impairment (8.6) and Clinical Pharmacology (12.3)].. 2.6Recommended Dosage for Severe Hepatic Impairment. The recommended dosage of PEMAZYRE for patients with severe hepatic impairment (total bilirubin 3 ULN with any AST) is mg orally once daily for 14 consecutive days followed by days off therapy, in 21-day cycles [see Hepatic Impairment (8.7) and Clinical Pharmacology (12.3)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed elsewhere in the labeling:Ocular Toxicity [see Warnings and Precautions 5.1 )] Hyperphosphatemia and Soft Tissue Mineralization [see Warnings and Precautions 5.2 )] Ocular Toxicity [see Warnings and Precautions 5.1 )] Hyperphosphatemia and Soft Tissue Mineralization [see Warnings and Precautions 5.2 )] The most common adverse reactions (incidence >= 20%) are hyperphosphatemia, alopecia, diarrhea, nail toxicity, fatigue, dysgeusia, nausea, constipation, stomatitis, dry eye, dry mouth, decreased appetite, vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Incyte Corporation at 1-855-463-3463 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety of PEMAZYRE was evaluated in FIGHT-202, which included 146 patients with previously treated, locally advanced or metastatic cholangiocarcinoma [see Clinical Studies 14.1 )]. Patients were treated orally with PEMAZYRE 13.5 mg once daily for 14 days on followed by days off therapy until disease progression or unacceptable toxicity. The median duration of treatment was 181 days (range: to 730 days).The median age of PEMAZYRE treated patients was 59 years (range 26-78), 58% were females, and 71% were White.Serious adverse reactions occurred in 45% of patients receiving PEMAZYRE. Serious adverse reactions in >= 2% of patients who received PEMAZYRE included abdominal pain, pyrexia, cholangitis, pleural effusion, acute kidney injury, cholangitis infective, failure to thrive, hypercalcemia, hyponatremia, small intestinal obstruction, and urinary tract infection. Fatal adverse reactions occurred in 4.1% of patients, including failure to thrive, bile duct obstruction, cholangitis, sepsis, and pleural effusion.Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received PEMAZYRE. Adverse reactions requiring permanent discontinuation in >=1% of patients included intestinal obstruction and acute kidney injury.Dosage interruptions due to an adverse reaction occurred in 43% of patients who received PEMAZYRE. Adverse reactions requiring dosage interruption in >= 1% of patients included stomatitis, palmar-plantar erythrodysesthesia syndrome, arthralgia, fatigue, abdominal pain, AST increased, asthenia, pyrexia, ALT increased, cholangitis, small intestinal obstruction, alkaline phosphatase increased, diarrhea, hyperbilirubinemia, electrocardiogram QT prolonged, decreased appetite, dehydration, hypercalcemia, hyperphosphatemia, hypophosphatemia, back pain, pain in extremity, syncope, acute kidney injury, onychomadesis, and hypotension.Dose reductions due to an adverse reaction occurred in 14% of patients who received PEMAZYRE. Adverse reactions requiring dosage reductions in >=1% of patients who received PEMAZYRE included stomatitis, arthralgia, palmar-plantar erythrodysesthesia syndrome, asthenia, and onychomadesis.Table summarizes the adverse reactions in FIGHT-202. Table summarizes laboratory abnormalitiesin FIGHT-202.Table 3: Adverse Reactions (>= 15%) in Patients Receiving PEMAZYRE in FIGHT-202 PEMAZYRE(N=146) Adverse Reaction All GradesGraded per NCI CTCAE 4.03. (%)Grades >= 3Only Grades - were identified. (%) Metabolism and nutrition disorders HyperphosphatemiaIncludes hyperphosphatemia and blood phosphorous increased; graded based on clinical severity and medical interventions taken according to the investigations-other, specify category in NCI CTCAE v4.03. 600 Decreased appetite331.4 HypophosphatemiaIncludes hypophosphatemia and blood phosphorous decreased. 2312 Dehydration153.4 Skin and subcutaneous tissue disorders Alopecia49 Nail toxicityIncludes nail toxicity, nail disorder, nail discoloration, nail dystrophy, nail hypertrophy, nail ridging, nail infection, onychalgia, onychoclasis, onycholysis, onychomadesis, onychomycosis, and paronychia. 432.1 Dry skin200.7 Palmar-plantar erythrodysesthesia syndrome154.1 Gastrointestinal disorders Diarrhea472.7 Nausea402.1 Constipation350.7 Stomatitis355 Dry mouth340 Vomiting271.4 Abdominal pain234.8 General disorders Fatigue424.8 Edema peripheral180.7 Nervous system disorders Dysgeusia400 Headache160 Eye disorders Dry eyeIncludes dry eye, keratitis, lacrimation increased, pinguecula, and punctate keratitis. 350.7 Musculoskeletal and connective tissue disorders Arthralgia256 Back pain202.7 Pain in extremity192.1 Infections and infestations Urinary tract infection 162.7 Investigations Weight loss 162.1Clinically relevant adverse reactions occurring in <= 10% of patients included fractures (2.1%). In all patients treated with pemigatinib, 1.3% experienced pathologic fractures (which included patients with and without cholangiocarcinoma [N=466]). Soft tissue mineralization, including cutaneous calcification, calcinosis, and non-uremic calciphylaxis associated with hyperphosphatemia were observed with PEMAZYRE treatment.Table 4: Select Laboratory Abnormalities (>= 10%) Worsening from Baseline in Patients Receiving PEMAZYRE in FIGHT-202 PEMAZYREThe denominator used to calculate the rate varied from 142-146 based on the number of patients with baseline value and at least one post-treatment value. (N=146) Laboratory Abnormality All GradesGraded per NCI CTCAE 4.03. (%) Grades >= (%) Hematology Decreased hemoglobin436 Decreased lymphocytes368 Decreased platelets283.4 Increased leukocytes270.7 Decreased leukocytes181.4 Chemistry Increased phosphateBased on CTCAE 5.0 grading. 940 Decreased phosphate6838 Increased alanine aminotransferase434.1 Increased aspartate aminotransferase436 Increased calcium434.1 Increased alkaline phosphatase4111 Increased creatinineGraded based on comparison to upper limit of normal. 411.4 Decreased sodium3912 Increased glucose360.7 Decreased albumin340 Increased urate3010 Increased bilirubin266 Decreased potassium265 Decreased calcium172.7 Increased potassium122.1 Decreased glucose111.4Increased CreatinineWithin the first 21-day cycle of PEMAZYRE dosing, serum creatinine increased (mean increase of 0.2 mg/dL) and reached steady state by Day 8, and then decreased during the days off therapy. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology 12.3 )].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Pemigatinib is small molecule kinase inhibitor that targets FGFR1, and with IC50 values of less than nM. Pemigatinib also inhibited FGFR4 in vitro at concentration approximately 100 times higher than those that inhibit FGFR1, 2, and 3. Pemigatinib inhibited FGFR1-3 phosphorylation and signaling and decreased cell viability in cancer cell lines with activating FGFR amplifications and fusions that resulted in constitutive activation of FGFR signaling. Constitutive FGFR signaling can support the proliferation and survival of malignant cells. Pemigatinib exhibited anti-tumor activity in mouse xenograft models of human tumors with FGFR1, FGFR2, or FGFR3 alterations resulting in constitutive FGFR activation including patient-derived xenograft model of cholangiocarcinoma that expressed an oncogenic FGFR2-Transformer-2 beta homolog (TRA2b) fusion protein.. 12.2 Pharmacodynamics. Serum PhosphatePemigatinib increased serum phosphate levels as consequence of FGFR inhibition. Serum phosphate increased with increasing exposure across the dose range of to 20 mg once daily (0.07 to 1.5 times the recommended dose), with increased risk of hyperphosphatemia with higher pemigatinib exposure.Cardiac ElectrophysiologyAt dose 1.5 times the maximum recommended dose, PEMAZYRE does not result in large mean increase (i.e. >20 ms) of the QTc interval.. 12.3 Pharmacokinetics. The geometric mean (CV%) steady-state pemigatinib AUC0-24h was 2620 nM.h (54%) and Cmax was 236 nM (56%) for 13.5 mg orally once daily. Steady state pemigatinib concentrations increased proportionally over the dose range of to 20 mg (0.07 to 1.5 times the recommended dose). Steady-state was achieved within days and pemigatinib accumulated with median accumulation ratio of 1.63 (range 0.63 to 3.28) following repeated once daily dosing. AbsorptionThe median time to achieve peak pemigatinib plasma concentration (Tmax) was 1.13 (0.50-6.00) hours.Effect of FoodAdministration of PEMAZYRE with high-fat and high-calorie meal (approximately 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500-600 calories from fat) had no clinically significant effect on pemigatinib pharmacokinetics.DistributionThe estimated apparent volume of distribution was 235 (60.8%) following 13.5 mg oral dose. Protein binding of pemigatinib was 90.6% and was independent of concentration in vitro.EliminationThe geometric mean (%CV) elimination half-life (t 1/2 of pemigatinib was 15.4 (51.6%) hours and the geometric mean apparent clearance (CL/F) was 10.6 L/h (54%).MetabolismPemigatinib is predominantly metabolized by CYP3A4 in vitro. The major drug-related moiety in plasma was unchanged pemigatinib.ExcretionFollowing single oral 11 mg dose of radiolabeled pemigatinib, 82.4% of the dose was recovered in feces (1.4% as unchanged) and 12.6% in urine (1% as unchanged).Specific PopulationsNo clinically significant differences in the systemic exposure of pemigatinib were observed based on age (21 79 years), sex, race/ethnicity (White 68.2%, Asian 16%, Black 6.3%, Hispanic 6%, other 3.5%) or body weight (39.8 156 kg). Patients with Renal Impairment No clinically significant differences in the systemic exposure of pemigatinib were observed in mild to moderate renal impairment (eGFR 30 to 89 mL/min, MDRD) or end-stage renal disease (eGFR <15 mL/min/1.73 m2) on intermittent hemodialysis. Compared to subjects with normal renal function, the geometric mean pemigatinib AUC0-inf increased by 59% in patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2).Patients with Hepatic Impairment No clinically significant differences in the systemic exposure of pemigatinib were observed in mild (total bilirubin upper limit of normal [ULN] to 1.5 ULN or AST ULN) to moderate (total bilirubin >1.5-3 ULN with any AST) hepatic impairment. Compared to subjects with normal hepatic function, the geometric mean pemigatinib AUC0-inf increased by 136% in subjects with severe hepatic impairment (total bilirubin 3 ULN with any AST).Drug Interaction StudiesClinical Studies and Model-Based ApproachesCYP3A Inhibitors: Itraconazole (strong CYP3A inhibitor) increased Cmax by 17% and increased AUC by 88% following single oral PEMAZYRE dose of 4.5 mg [see Drug Interactions 7.1 )]. Concomitant use of moderate CYP3A inhibitors is predicted to increase pemigatinib exposure by approximately 50-80% [see Drug Interactions 7.1 )].CYP3A Inducers: Rifampin (strong CYP3A inducer) decreased pemigatinib Cmax by 62% and AUC by 85% following single oral PEMAZYRE dose of 13.5 mg [see Drug Interactions 7.1 )]. Concomitant use of moderate CYP3A inducer is predicted to decrease pemigatinib exposure by more than 50% [see Drug Interactions 7.1 )].Other Drugs: No clinically significant differences in pemigatinib exposure when co-administered with esomeprazole (proton pump inhibitor) or ranitidine (histamine-2 antagonist). No clinically significant differences in glucose levels were observed when metformin (OCT2/MATE1 substrate) was co-administered with pemigatinib.In Vitro StudiesCYP Enzymes: Pemigatinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 or an inducer of CYP1A2, CYP2B6, or CYP3A4.Transporter Systems: Pemigatinib is substrate of both P-gp and BCRP. P-gp or BCRP inhibitors are not expected to affect pemigatinib exposure at clinically relevant concentrations. Pemigatinib is an inhibitor of P-gp, OCT2, and MATE1. Pemigatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine; this may occur due to inhibition of renal transporters OCT2 and MATE1 and may not affect glomerular function [see Adverse Reactions (6.1)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Cholangiocarcinoma. FIGHT-202 (NCT02924376), multicenter open-label single-arm trial, evaluated the efficacy of PEMAZYRE in 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease had progressed on or after at least prior therapy and who had an FGFR2 gene fusion or non-fusion rearrangement, as determined by clinical trial assay performed at central laboratory. Qualifying in-frame fusions and other rearrangements were predicted to have breakpoint within intron 17/exon 18 of the FGFR2 gene leaving the FGFR2 kinase domain intact.Patients received PEMAZYRE in 21-day cycles at dosage of 13.5 mg orally once daily for 14 consecutive days, followed by days off therapy. PEMAZYRE was administered until disease progression or unacceptable toxicity. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1.The median age was 56 years (range: 26 to 77 years), 61% were female, 74% were White, and 95% had baseline Eastern Cooperative Oncology Group (ECOG) performance status of (42%) or (53%). Ninety-eight percent of patients had intrahepatic cholangiocarcinoma. Eighty-six percent of patients had in-frame FGFR2 gene fusions and the most commonly identified FGFR2 fusion was FGFR2-BICC1 (34%). Fourteen percent of patients had other FGFR2 rearrangements that could not be confidently predicted to be in-frame fusions, including rearrangements without an identifiable partner gene. All patients had received at least prior line of systemic therapy, 27% had prior lines of therapy, and 12% had or more prior lines of therapy. Ninety-six percent of patients had received prior platinum-based therapy including 76% with prior gemcitabine/cisplatin.Efficacy results are summarized in Table 5.The median time to response was 2.7 months (range 0.7 6.9 months).Table 5: Efficacy Results in FIGHT-202 Efficacy ParameterPEMAZYREN 107 ORR (95% CI)36% (27, 45) Complete response 2.8% Partial response 33% Median DoR (months) (95% CI)The 95% confidence interval (CI) was calculated using the Brookmeyer and Crowleys method. Note: Data are from IRC per RECIST v1.1, and complete and partial responses are confirmed. 9.1 (6.0, 14.5) Patients with DoR >= months, (%)24 (63%) Patients with DoR >= 12 months, (%)7 (18%).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Ocular ToxicityAdvise patients that PEMAZYRE may cause ocular toxicity including RPED and to immediately inform their healthcare provider if they experience any visual changes. Also advise patients that they should use artificial tear or substitutes, hydrating or lubricating eye gels in order to prevent or treat dry eyes [see Warnings and Precautions 5.1 )].Hyperphosphatemia and Soft Tissue MineralizationInform patients that they may experience increase in phosphate levels and of the need to monitor serum phosphate levels. Advise patients to immediately inform their healthcare provider of any symptoms related to acute change in phosphate levels such as muscle cramps, numbness, or tingling around the mouth [see Warnings and Precautions 5.2 )].Nail DisordersAdvise patients that PEMAZYRE may cause nail disorders [see Adverse Reactions 6.1 )].Embryo-Fetal ToxicityAdvise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to fetus and potential loss of pregnancy[see Warnings and Precautions 5.3 and Use in Specific Populations 8.1 )].Advise females of reproductive potential to use effective contraception during treatment with PEMAZYRE and for week after the final dose see Use in Specific Populations 8.3 )].Advise males with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for week after receiving the final dose of PEMAZYRE[see Use in Specific Populations 8.3 )]. LactationAdvise patients not to breastfeed during treatment with PEMAZYRE and for week after the final dose [see Use in Specific Populations 8.2 )].AdministrationInstruct patients do not crush, chew, split or dissolve tablets.Instruct patients if they miss dose by or more hours or if they vomit after taking dose, resume dosing with the next scheduled dose. Extra tablets should not be taken to make up for the missed dose [see Dosage and Administration 2.2)]. Drug Interactions Advise patients to inform their healthcare providers of all concomitant medications, herbal and dietary supplements. Advise patients to avoid grapefruit products during treatment with PEMAZYRE [see Drug Interactions (7.1)].Manufactured for: Incyte Corporation Wilmington, DE 19803PEMAZYRE is registered trademark of Incyte.U.S. Patent Nos. 9,611,267 and 10,131,667(C) 2020-2021 Incyte Corporation. All rights reserved.. Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to fetus and potential loss of pregnancy[see Warnings and Precautions 5.3 and Use in Specific Populations 8.1 )].. Advise females of reproductive potential to use effective contraception during treatment with PEMAZYRE and for week after the final dose see Use in Specific Populations 8.3 )].. Advise males with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for week after receiving the final dose of PEMAZYRE[see Use in Specific Populations 8.3 )]. Advise patients not to breastfeed during treatment with PEMAZYRE and for week after the final dose [see Use in Specific Populations 8.2 )].. Instruct patients do not crush, chew, split or dissolve tablets.. Instruct patients if they miss dose by or more hours or if they vomit after taking dose, resume dosing with the next scheduled dose. Extra tablets should not be taken to make up for the missed dose [see Dosage and Administration 2.2)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The geometric mean (CV%) steady-state pemigatinib AUC0-24h was 2620 nM.h (54%) and Cmax was 236 nM (56%) for 13.5 mg orally once daily. Steady state pemigatinib concentrations increased proportionally over the dose range of to 20 mg (0.07 to 1.5 times the recommended dose). Steady-state was achieved within days and pemigatinib accumulated with median accumulation ratio of 1.63 (range 0.63 to 3.28) following repeated once daily dosing. AbsorptionThe median time to achieve peak pemigatinib plasma concentration (Tmax) was 1.13 (0.50-6.00) hours.Effect of FoodAdministration of PEMAZYRE with high-fat and high-calorie meal (approximately 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500-600 calories from fat) had no clinically significant effect on pemigatinib pharmacokinetics.DistributionThe estimated apparent volume of distribution was 235 (60.8%) following 13.5 mg oral dose. Protein binding of pemigatinib was 90.6% and was independent of concentration in vitro.EliminationThe geometric mean (%CV) elimination half-life (t 1/2 of pemigatinib was 15.4 (51.6%) hours and the geometric mean apparent clearance (CL/F) was 10.6 L/h (54%).MetabolismPemigatinib is predominantly metabolized by CYP3A4 in vitro. The major drug-related moiety in plasma was unchanged pemigatinib.ExcretionFollowing single oral 11 mg dose of radiolabeled pemigatinib, 82.4% of the dose was recovered in feces (1.4% as unchanged) and 12.6% in urine (1% as unchanged).Specific PopulationsNo clinically significant differences in the systemic exposure of pemigatinib were observed based on age (21 79 years), sex, race/ethnicity (White 68.2%, Asian 16%, Black 6.3%, Hispanic 6%, other 3.5%) or body weight (39.8 156 kg). Patients with Renal Impairment No clinically significant differences in the systemic exposure of pemigatinib were observed in mild to moderate renal impairment (eGFR 30 to 89 mL/min, MDRD) or end-stage renal disease (eGFR <15 mL/min/1.73 m2) on intermittent hemodialysis. Compared to subjects with normal renal function, the geometric mean pemigatinib AUC0-inf increased by 59% in patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2).Patients with Hepatic Impairment No clinically significant differences in the systemic exposure of pemigatinib were observed in mild (total bilirubin upper limit of normal [ULN] to 1.5 ULN or AST ULN) to moderate (total bilirubin >1.5-3 ULN with any AST) hepatic impairment. Compared to subjects with normal hepatic function, the geometric mean pemigatinib AUC0-inf increased by 136% in subjects with severe hepatic impairment (total bilirubin 3 ULN with any AST).Drug Interaction StudiesClinical Studies and Model-Based ApproachesCYP3A Inhibitors: Itraconazole (strong CYP3A inhibitor) increased Cmax by 17% and increased AUC by 88% following single oral PEMAZYRE dose of 4.5 mg [see Drug Interactions 7.1 )]. Concomitant use of moderate CYP3A inhibitors is predicted to increase pemigatinib exposure by approximately 50-80% [see Drug Interactions 7.1 )].CYP3A Inducers: Rifampin (strong CYP3A inducer) decreased pemigatinib Cmax by 62% and AUC by 85% following single oral PEMAZYRE dose of 13.5 mg [see Drug Interactions 7.1 )]. Concomitant use of moderate CYP3A inducer is predicted to decrease pemigatinib exposure by more than 50% [see Drug Interactions 7.1 )].Other Drugs: No clinically significant differences in pemigatinib exposure when co-administered with esomeprazole (proton pump inhibitor) or ranitidine (histamine-2 antagonist). No clinically significant differences in glucose levels were observed when metformin (OCT2/MATE1 substrate) was co-administered with pemigatinib.In Vitro StudiesCYP Enzymes: Pemigatinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 or an inducer of CYP1A2, CYP2B6, or CYP3A4.Transporter Systems: Pemigatinib is substrate of both P-gp and BCRP. P-gp or BCRP inhibitors are not expected to affect pemigatinib exposure at clinically relevant concentrations. Pemigatinib is an inhibitor of P-gp, OCT2, and MATE1. Pemigatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine; this may occur due to inhibition of renal transporters OCT2 and MATE1 and may not affect glomerular function [see Adverse Reactions (6.1)].

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION PEMAZYRE(R) pemah zeer (pemigatinib) tablets What is PEMAZYRE PEMAZYRE is prescription medicine that is used to treat adults with bile duct cancer (cholangiocarcinoma) that has spread or cannot be removed by surgery: who have already received previous treatment, and whose tumor has certain type of abnormal FGFR2 gene. Your healthcare provider will test your cancer for certain type of abnormal FGFR2 gene and make sure that PEMAZYRE is right for you. It is not known if PEMAZYRE is safe and effective in children. Before you take PEMAZYRE, tell your healthcare provider about all of your medical conditions, including if you: have vision or eye problemshave kidney problemshave liver problems are pregnant or plan to become pregnant. PEMAZYRE can harm your unborn baby or cause loss of your pregnancy (miscarriage). You should not become pregnant during treatment with PEMAZYRE. Females who can become pregnant: Your healthcare provider should do pregnancy test before you start treatment with PEMAZYRE. You should use an effective method of birth control during treatment and for week after your final dose of PEMAZYRE. Talk to your healthcare provider about birth control methods that may be right for you. Tell your healthcare provider right away if you become pregnant or think that you may be pregnant. Males with female partners who can become pregnant: You should use effective birth control when sexually active during treatment with PEMAZYRE and for week after your final dose of PEMAZYRE. are breastfeeding or plan to breastfeed. It is not known if PEMAZYRE passes into your breast milk. Do not breastfeed during treatment and for week after your final dose of PEMAZYRE. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should take PEMAZYRE Take PEMAZYRE exactly as your healthcare provider tells you.PEMAZYRE is taken in cycles of 21 days. Take PEMAZYRE time each day for 14 days, followed by days off treatment, to complete 21-day treatment cycle.Take PEMAZYRE time each day at about the same time each day. Take PEMAZYRE with or without food.Swallow tablets whole. Do not crush, chew, split, or dissolve PEMAZYRE tablets.You should not eat or drink grapefruit products during treatment with PEMAZYRE.Your healthcare provider may change your dose of PEMAZYRE, or may temporarily or completely stop treatment if you get certain side effects.If you miss dose of PEMAZYRE, you can take the missed dose within hours on the same day. If more than hours have passed, do not make up the dose. Take your regular dose of PEMAZYRE the next day at the usual time. Do not take more PEMAZYRE than prescribed to make up for the missed dose.If you vomit after taking PEMAZYRE, do not take another PEMAZYRE tablet. Take your regular dose of PEMAZYRE the next day at the usual time. What are the possible side effects of PEMAZYRE PEMAZYRE may cause serious side effects, including:Eye problems. Certain eye problems are common with PEMAZYRE but can also be serious. Eye problems include dry eye or inflamed eyes, inflamed cornea (front part of the eye), increased tears, and disorder of the retina (an internal part of the eye). You will need to see an eye specialist for complete eye exam before you begin treatment with PEMAZYRE, every months for the first months, and then every months during treatment with PEMAZYRE.You should use artificial tears or substitutes, hydrating or lubricating eye gels as needed, to help prevent or treat dry eyes.Tell your healthcare provider right away if you develop any changes in your vision during treatment with PEMAZYRE, including: blurred vision, flashes of light, or see black spots. You may need to see an eye specialist right away.High phosphate levels in your blood (hyperphosphatemia) and buildup of minerals in different tissues in your body. Hyperphosphatemia is common with PEMAZYRE but can also be serious. High levels of phosphate in your blood may lead to buildup of minerals such as calcium, in different tissues in your body. Your healthcare provider will check your blood phosphate levels during treatment with PEMAZYRE.Your healthcare provider may prescribe changes in your diet or phosphate lowering therapy, or change, interrupt or stop PEMAZYRE if needed.Tell your healthcare provider right away if you develop any muscle cramps, or numbness or tingling around your mouth. The most common side effects of PEMAZYRE include:hair loss diarrhea nails separate from the bed or poor formation of the nailfeeling tiredchange in sense of tastenauseaconstipationmouth soresdry eyesdry mouthdecrease in appetitevomiting joint painstomach-area (abdominal) painlow phosphate in blood back paindry skin These are not all the possible side effects of PEMAZYRE. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store PEMAZYREStore PEMAZYRE at room temperature between 68F to 77F (20C to 25C).Keep PEMAZYRE and all medicines out of the reach of children.General information about the safe and effective use of PEMAZYRE Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use PEMAZYRE for condition for which it is not prescribed. Do not give PEMAZYRE to other people, even if they have the same symptoms you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information that is written for healthcare professionals.What are the ingredients in PEMAZYRE Active ingredient: pemigatinib Inactive ingredients: magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.Manufactured for: Incyte Corporation, Wilmington, DE 19803PEMAZYRE is registered trademark of Incyte. (C) 2020-2021 Incyte Corporation. All rights reserved. For more information, call Incyte at 1-855-463-3463 or go to www.PEMAZYRE.comThis Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 06/2021. who have already received previous treatment, and whose tumor has certain type of abnormal FGFR2 gene. have vision or eye problems. have kidney problems. have liver problems. are pregnant or plan to become pregnant. PEMAZYRE can harm your unborn baby or cause loss of your pregnancy (miscarriage). You should not become pregnant during treatment with PEMAZYRE. Females who can become pregnant: Your healthcare provider should do pregnancy test before you start treatment with PEMAZYRE. You should use an effective method of birth control during treatment and for week after your final dose of PEMAZYRE. Talk to your healthcare provider about birth control methods that may be right for you. Tell your healthcare provider right away if you become pregnant or think that you may be pregnant. Males with female partners who can become pregnant: You should use effective birth control when sexually active during treatment with PEMAZYRE and for week after your final dose of PEMAZYRE.. are breastfeeding or plan to breastfeed. It is not known if PEMAZYRE passes into your breast milk. Do not breastfeed during treatment and for week after your final dose of PEMAZYRE.. Take PEMAZYRE exactly as your healthcare provider tells you.. PEMAZYRE is taken in cycles of 21 days. Take PEMAZYRE time each day for 14 days, followed by days off treatment, to complete 21-day treatment cycle.. Take PEMAZYRE time each day at about the same time each day. Take PEMAZYRE with or without food.. Swallow tablets whole. Do not crush, chew, split, or dissolve PEMAZYRE tablets.. You should not eat or drink grapefruit products during treatment with PEMAZYRE.. Your healthcare provider may change your dose of PEMAZYRE, or may temporarily or completely stop treatment if you get certain side effects.. If you miss dose of PEMAZYRE, you can take the missed dose within hours on the same day. If more than hours have passed, do not make up the dose. Take your regular dose of PEMAZYRE the next day at the usual time. Do not take more PEMAZYRE than prescribed to make up for the missed dose.. If you vomit after taking PEMAZYRE, do not take another PEMAZYRE tablet. Take your regular dose of PEMAZYRE the next day at the usual time.. Eye problems. Certain eye problems are common with PEMAZYRE but can also be serious. Eye problems include dry eye or inflamed eyes, inflamed cornea (front part of the eye), increased tears, and disorder of the retina (an internal part of the eye). You will need to see an eye specialist for complete eye exam before you begin treatment with PEMAZYRE, every months for the first months, and then every months during treatment with PEMAZYRE.You should use artificial tears or substitutes, hydrating or lubricating eye gels as needed, to help prevent or treat dry eyes.Tell your healthcare provider right away if you develop any changes in your vision during treatment with PEMAZYRE, including: blurred vision, flashes of light, or see black spots. You may need to see an eye specialist right away.. You should use artificial tears or substitutes, hydrating or lubricating eye gels as needed, to help prevent or treat dry eyes.. Tell your healthcare provider right away if you develop any changes in your vision during treatment with PEMAZYRE, including: blurred vision, flashes of light, or see black spots. You may need to see an eye specialist right away.. High phosphate levels in your blood (hyperphosphatemia) and buildup of minerals in different tissues in your body. Hyperphosphatemia is common with PEMAZYRE but can also be serious. High levels of phosphate in your blood may lead to buildup of minerals such as calcium, in different tissues in your body. Your healthcare provider will check your blood phosphate levels during treatment with PEMAZYRE.Your healthcare provider may prescribe changes in your diet or phosphate lowering therapy, or change, interrupt or stop PEMAZYRE if needed.Tell your healthcare provider right away if you develop any muscle cramps, or numbness or tingling around your mouth. Your healthcare provider may prescribe changes in your diet or phosphate lowering therapy, or change, interrupt or stop PEMAZYRE if needed.. Tell your healthcare provider right away if you develop any muscle cramps, or numbness or tingling around your mouth.. hair loss diarrhea nails separate from the bed or poor formation of the nail. feeling tired. change in sense of taste. nausea. constipation. mouth sores. dry eyes. dry mouth. decrease in appetite. vomiting joint pain. stomach-area (abdominal) pain. low phosphate in blood back pain. dry skin Store PEMAZYRE at room temperature between 68F to 77F (20C to 25C).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings in an animal study and its mechanism of action, PEMAZYRE can cause fetal harm or loss of pregnancy when administered to pregnant woman [see Clinical Pharmacology 12.1 )]. There are no available data on the use of PEMAZYRE in pregnant women. Oral administration of pemigatinib to pregnant rats during the period of organogenesis at maternal plasma exposures below the human exposure at the clinical dose of 13.5 mg resulted in fetal malformations, fetal growth retardation, and embryo-fetal death (see Data). Advise pregnant women of the potential risk to fetus.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.DataAnimal DataOnce daily oral administration of pemigatinib to pregnant rats during the period of organogenesis resulted in 100% embryofetal mortality due to post-implantation loss at doses >= 0.3 mg/kg (approximately 0.6 times the human exposure based on AUC at the clinical dose of 13.5 mg). Fetal survival was unaffected at 0.1 mg/kg per day; however, once daily oral administration of pemigatinib at the 0.1 mg/kg dose level (approximately 0.2 times the human exposure based on AUC at the clinical dose of 13.5 mg) resulted in reduced mean fetal body weight and an increase in fetal skeletal and visceral malformations, major blood vessel variations, and reduced ossification.. 8.2 Lactation. Risk SummaryThere are no data on the presence of pemigatinib or its metabolites in human milk or their effects on either the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children from PEMAZYRE, advise women not to breastfeed during treatment and for week after the final dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status of females of reproductive potential prior to initiating PEMAZYRE [see Use in Specific Populations 8.1 )].ContraceptionPEMAZYRE can cause fetal harm when administered to pregnant women [see Use in Specific Populations 8.1 )]. FemalesAdvise females of reproductive potential to use effective contraception during treatment with PEMAZYRE and for week after the final dose.MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for week after the final dose.. 8.4 Pediatric Use. The safety and effectiveness of PEMAZYRE have not been established in pediatric patients.Animal Toxicity DataIn 4- or 13-week repeat-dose toxicology studies in rats and non-human primates, animals displayed toxicities in bone and teeth at pemigatinib exposures lower than the human exposure at the clinical dose of 13.5 mg. Physeal and cartilage dysplasia were present in multiple bones in both species, and tooth (incisor) abnormalities (complete loss of ameloblasts with associated secondary changes) occurred in rats. Six weeks after cessation of dosing, these findings did not show complete evidence of recovery, and additional tooth-related findings (mal-aligned, whitened, broken, and trimmed/thinned incisors) developed in the 13-week study.. 8.5 Geriatric Use. In FIGHT-202, 32% of patients were 65 years and older, and 8% of patients were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.. 8.6 RenalImpairment. Reduce the recommended dosage of PEMAZYRE for patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2, estimated by Modification of Diet in Renal Disease [MDRD] equation) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].No dosage adjustment is recommended for patients with mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2). No dosage adjustment is recommended for patients with end-stage renal disease (eGFR 15 mL/min/1.73 m2) who are receiving intermittent hemodialysis. see Clinical Pharmacology 12.3 )].. 8.7 Hepatic Impairment. Reduce the recommended dosage of PEMAZYRE for patients with severe hepatic impairment (total bilirubin 3 ULN with any AST) [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].No dosage adjustment is recommended for patients with mild (total bilirubin upper limit of normal [ULN] to 1.5 ULN or AST ULN) or moderate (total bilirubin >1.5-3 ULN with any AST) hepatic impairment see Clinical Pharmacology 12.3 )].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Ocular Toxicity: PEMAZYRE can cause retinal pigment epithelial detachment. Perform ophthalmological examination including optical coherence tomography (OCT) prior to initiation of therapy, every months for the first months of treatment and every months thereafter, and urgently at any time for visual symptoms. (2.3, 5.1)Hyperphosphatemia and Soft Tissue Mineralization: PEMAZYRE can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcification, calcinosis, and non-uremic calciphylaxis. Monitor for hyperphosphatemia and withhold, reduce the dose, or permanently discontinue based on duration and severity of hyperphosphatemia. (2.3, 5.2)Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to the fetus and use effective contraception. (5.3, 8.1, 8.3). Ocular Toxicity: PEMAZYRE can cause retinal pigment epithelial detachment. Perform ophthalmological examination including optical coherence tomography (OCT) prior to initiation of therapy, every months for the first months of treatment and every months thereafter, and urgently at any time for visual symptoms. (2.3, 5.1). Hyperphosphatemia and Soft Tissue Mineralization: PEMAZYRE can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcification, calcinosis, and non-uremic calciphylaxis. Monitor for hyperphosphatemia and withhold, reduce the dose, or permanently discontinue based on duration and severity of hyperphosphatemia. (2.3, 5.2). Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to the fetus and use effective contraception. (5.3, 8.1, 8.3). 5.1 OcularToxicity. Retinal Pigment Epithelial Detachment (RPED)PEMAZYRE can cause RPED, which may cause symptoms such as blurred vision, visual floaters, or photopsia. Clinical trials of PEMAZYRE did not conduct routine monitoring including optical coherence tomography (OCT) to detect asymptomatic RPED; therefore, the incidence of asymptomatic RPED with PEMAZYRE is unknown.Among 466 patients who received PEMAZYRE across clinical trials, RPED occurred in 6% of patients, including Grade 3-4 RPED in 0.6%. The median time to first onset of RPED was 62 days. RPED led to dose interruption of PEMAZYRE in 1.7% of patients, and dose reduction and permanent discontinuation in 0.4% and in 0.4% of patients, respectively. RPED resolved or improved to Grade levels in 87.5% of patients who required dosage modification of PEMAZYRE for RPED.Perform comprehensive ophthalmological examination including OCT prior to initiation of PEMAZYRE and every months for the first months and every months thereafter during treatment. For onset of visual symptoms, refer patients for ophthalmologic evaluation urgently, with follow-up every weeks until resolution or discontinuation of PEMAZYRE.Modify the dose or permanently discontinue PEMAZYRE as recommended [see Dosage and Administration 2.3 )].Dry EyeAmong 466 patients who received PEMAZYRE across clinical trials, dry eye occurred in 27% of patients, including Grade 3-4 in 0.6% of patients. Treat patients with ocular demulcents as needed.. 5.2 Hyperphosphatemia and Soft Tissue Mineralization. PEMAZYRE can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcification, calcinosis, and non-uremic calciphylaxis. Increases in phosphate levels are pharmacodynamic effect of PEMAZYRE [see Clinical Pharmacology 12.2 ] Among 466 patients who received PEMAZYRE across clinical trials, hyperphosphatemia was reported in 92% of patients based on laboratory values above the upper limit of normal. The median time to onset of hyperphosphatemia was days (range 1-169). Phosphate lowering therapy was required in 29% of patients receiving PEMAZYRE.Monitor for hyperphosphatemia and initiate low phosphate diet when serum phosphate level is 5.5 mg/dL. For serum phosphate levels 7 mg/dL, initiate phosphate lowering therapy and withhold, reduce the dose, or permanently discontinue PEMAZYRE based on duration and severity of hyperphosphatemia [see Dosage and Administration 2.3 )]. 5.3 Embryo-Fetal Toxicity. Based on findings in an animal study and its mechanism of action, PEMAZYRE can cause fetal harm when administered to pregnant woman. Oral administration of pemigatinib to pregnant rats during the period of organogenesis caused fetal malformations, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure based on area under the curve (AUC) at the clinical dose of 13.5 mg.Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with PEMAZYRE and for week after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for week after the final dose [see Use in Specific Populations 8.1 8.3 )].