U.S. FDA APPROVED  DRUGS DURING 2020

Sr.No-  14

ADVERSE REACTIONS 

17. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Ocular Toxicity Advise 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 Inform patients that they may experience increase in phosphate levels and of the need to monitor serum phosphate levels. They should immediately inform their healthcare provider of any 16 Reference ID: 4591160 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 Disorders Advise patients that PEMAZYRE may cause nail disorders [see Adverse Reactions (6.1)]. Embryo-Fetal Toxicity ? Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a 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 1 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 1 week after receiving the final dose of PEMAZYRE[see Use in Specific Populations (8.3)]. Lactation ? Advise patients not to breastfeed during treatment with PEMAZYRE and for 1 week after the final dose [see Use in Specific Populations (8.2)]. Administration ? Instruct patients do not crush, chew, split or dissolve tablets. ? Instruct patients if they miss a dose by 4 or more hours or if they vomit after taking a 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 19803 PEMAZYRE is a trademark of Incyte Corporation. U.S. Patent Nos. 9,611,267 and 10,131,667 © 2020 Incyte Corporation. All rights reserved.

12. CLINICAL PHARMACOLOGY 12.1. Mechanism of Action Pemigatinib is a small molecule kinase inhibitor that targets FGFR1, 2 and 3 with IC50 values of less than 2 nM. Pemigatinib also inhibited FGFR4 in vitro at a 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 12 Reference ID: 4591160 FGFR1, FGFR2, or FGFR3 alterations resulting in constitutive FGFR activation including a patient-derived xenograft model of cholangiocarcinoma that expressed an oncogenic FGFR2­ Transformer-2 beta homolog (TRA2b) fusion protein. 12.2. Pharmacodynamics Cardiac Electrophysiology At a dose 1.5 times the maximum recommended dose, PEMAZYRE does not result in a large mean increase (i.e. >20 ms) of the QTc interval. Serum Phosphate Pemigatinib increased serum phosphate levels as a consequence of FGFR inhibition. In patients, the increase in serum phosphate observed after treatment with pemigatinib was exposuredependent across the dose range of 1 to 20 mg once daily (0.07 to 1.5 times the recommended dose), with increased risk of hyperphosphatemia with higher pemigatinib exposure. 12.3. Pharmacokinetics The geometric mean steady-state pemigatinib AUC0-24h was 2620 nM·h (54% CV) and Cmax was 236 nM (56% CV) for 13.5 mg orally once daily. Steady state pemigatinib concentrations increased proportionally over the dose range of 1 to 20 mg (0.07 to 1.5 times the recommended dose). Steady-state was achieved within 4 days following repeated once daily dosing. With repeated once daily dosing, pemigatinib accumulated with a median accumulation ratio of 1.63 (range 0.63 to 3.28). Absorption The median time to achieve peak pemigatinib plasma concentration (Tmax) was 1.13 (0.50-6.00) hours. Effect of Food Administration of PEMAZYRE with a 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 meaningful effect on pemigatinib pharmacokinetics. Distribution The estimated apparent volume of distribution was 235 L (60.8%) following a 13.5 mg oral dose. In vitro, pemigatinib was 90.6% bound to human plasma proteins at concentrations ranging from 1 to 10 µM. Elimination The geometric mean elimination half-life (t½) of pemigatinib was 15.4 (51.6% CV) hours and the geometric mean apparent clearance (CL/F) was 10.6 L/h (54% CV). 13 Reference ID: 4591160 Metabolism Pemigatinib is predominantly metabolized by CYP3A4 in vitro. The major drug-related moiety in plasma was unchanged pemigatinib in a human [14C] mass balance study. Excretion Following a 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 Populations No clinically meaningful differences in the systemic exposure of pemigatinib were observed based on age (21 - 79 years), sex, race/ethnicity, body weight (39.8 - 156 kg), mild to moderate renal impairment, or mild to moderate hepatic impairment. The effect of severe renal impairment, renal dialysis in end-stage renal disease, or severe hepatic impairment on pemigatinib exposure is unknown. Drug Interaction Studies Clinical Studies and Model-Based Approaches Effect of CYP3A Inhibitors on Pemigatinib: Itraconazole, a strong CYP3A inhibitor, increased Cmax by 17% and increased AUC by 88% following a 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)]. Effect of CYP3A Inducers on Pemigatinib: Rifampin, a strong CYP3A inducer, decreased pemigatinib Cmax by 62% and AUC by 85% following a single oral PEMAZYRE dose of 13.5 mg [see Drug Interactions (7.1)]. Concomitant use of a moderate CYP3A inducer is predicted to decrease pemigatinib exposure by more than 50% [see Drug Interactions (7.1)]. Effect of Acid-Lowering Agents on Pemigatinib: Esomeprazole, a proton pump inhibitor, decreased pemigatinib Cmax by 35% and AUC by 8% following a single oral PEMAZYRE dose of 13.5 mg; these differences are not expected to be clinically meaningful. Ranitidine, a histamine-2 antagonist, did not affect pemigatinib exposure. Other Drugs: No clinically significant differences in glucose levels were observed when metformin (OCT2/MATE1 substrate) was co-administered with pemigatinib. In Vitro Studies Effect of Pemigatinib on CYP Enzymes: Pemigatinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 or an inducer of CYP1A2, CYP2B6, or CYP3A4. Pemigatinib as a Substrate for Transporters: Pemigatinib is a substrate of both P-gp and BCRP. P-gp or BCRP inhibitors are not expected to affect pemigatinib exposure at clinically relevant concentrations. 14 Reference ID: 4591160 Effect of Pemigatinib on Transporters: 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)].

13. NONCLINICAL TOXICOLOGY 13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with pemigatinib. Pemigatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in either an in vitro chromosome aberration assay or an in vivo micronucleus assay in rat

8. USE IN SPECIFIC POPULATIONS 8.1. Pregnancy Risk Summary Based on findings in an animal study and its mechanism of action, PEMAZYRE can cause fetal harm or loss of pregnancy when administered to a 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 a 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. Data Animal Data Once 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. 10 Reference ID: 4591160 8.2. Lactation Risk Summary There 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 1 week after the final dose. 8.3. Females and Males of Reproductive Potential Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating PEMAZYRE [see Use in Specific Populations (8.1)]. Contraception PEMAZYRE can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Females Advise females of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the final dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with PEMAZYRE and for 1 week after the final dose. 8.4. Pediatric Use The safety and effectiveness of PEMAZYRE have not been established in pediatric patients. Animal Toxicity Data In 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. 11 Reference ID: 4591160 8.6. Renal Impairment No dose adjustment is recommended for patients with mild or moderate renal impairment (glomerular filtration rate (GFR) = 30 to <90 mL/min estimated by Modification of Diet in Renal Disease (MDRD) equation). The recommended dose of PEMAZYRE has not been established for patients with severe renal impairment (GFR <30 mL/min) [see Clinical Pharmacology (12.3)]. 8.7. Hepatic Impairment No dose adjustment is recommended for patients with mild (total bilirubin > upper limit of normal (ULN) to 1.5 × ULN or AST > ULN) or moderate hepatic impairment (total bilirubin >1.5–3 × ULN with any AST). The recommended dose of PEMAZYRE has not been established for patients with severe hepatic impairment (total bilirubin >3 × ULN with any AST) [see Clinical Pharmacology (12.3)].

1. DESCRIPTION Pemigatinib is a kinase inhibitor with the chemical name 3-(2,6-difluoro-3,5-dimethoxyphenyl)­ 1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3',2':5,6]pyrido[4,3­ d]pyrimidin-2-one. Pemigatinib has a molecular formula of C24H27F2N5O4 and molecular mass of 487.5 g/mole. Pemigat