---------------------DRUG INTERACTIONS------------------------------- ? Strong and Moderate CYP3A Inhibitors: Avoid concomitant use. (7.1) ? P-gp inhibitors: Avoid concomitant use. (7.1) ? Strong and Moderate CYP3A Inducers: Avoid concomitant use. (7.1) ? Certain CYP3A Substrates: Avoid concomitant use with CYP3A substrates, where minimal concentration changes can cause reduced efficacy. (7.2) ? Hormonal contraceptives: Avoid concomitant use. (7.2)

---------------------DRUG INTERACTIONS------------------------------- ? Strong and Moderate CYP3A Inhibitors: Avoid concomitant use. (7.1) ? P-gp inhibitors: Avoid concomitant use. (7.1) ? Strong and Moderate CYP3A Inducers: Avoid concomitant use. (7.1) ? Certain CYP3A Substrates: Avoid concomitant use with CYP3A substrates, where minimal concentration changes can cause reduced efficacy. (7.2) ? Hormonal contraceptives: Avoid concomitant use. (7.2)

U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 49

Name-          AUGTYRO

Active ingedient-       Repotrectinib                 

Indication              to treat rosi positive non small cell lung cancer

Date  of approval       11/15/2023 

HIGHLIGHTS OF PRESCRIBING INFORMATION-

 These highlights do not include all the information needed to use                                     AUGTYRO safely and effectively.

See full prescribing information for AUGTYRO. AUGTYROTM (repotrectinib) capsules, for oral use

Initial U.S. Approval: 2023

INDICATIONS AND USAGE-

 AUGTYRO is a kinase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC).

DOSAGE AND ADMINISTRATION-

 Select patients for the treatment of locally advanced or metastatic NSCLC based on the presence of ROS1 rearrangement(s) in tumor specimens.

 Recommended Dosage: 160 mg orally once daily for 14 days, then increase to 160 mg twice daily, with or without food.

DOSAGE FORMS AND STRENGTHS--

 Capsules: 40 mg (3)

CONTRAINDICATIONS--

 None

WARNINGS AND PRECAUTIONS=

 Central Nervous System (CNS) Effects: Can cause CNS adverse reactions including dizziness, ataxia, and cognitive impairment. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity. (5.1) ? Interstitial Lung Disease (ILD)/Pneumonitis: Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. (5.2) ? Hepatotoxicity: Monitor liver function tests every 2 weeks during the first month of treatment, and as clinically indicated thereafter. Based on severity, withhold and then resume at same or reduced dose, or permanently discontinue. (5.3) ? Myalgia with Creatine Phosphokinase (CPK) Elevation: Monitor serum CPK levels during treatment in patients reporting unexplained muscle pain, tenderness, or weakness. Based on severity, withhold and resume at same or reduced dose upon improvement. (5.4) ? Hyperuricemia: Monitor serum uric acid levels prior to initiating and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold and resume at same or reduced dose, or permanently discontinue based on severity. (5.5) ? Skeletal Fractures: Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. (5.6) ? Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use an effective non-hormonal method of contraception. (5.7) ---------------------------

----ADVERSE REACTIONS------------------------------ The most common adverse reactions (=20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ------------------------------DRUG INTERACTIONS------------------------------- ? Strong and Moderate CYP3A Inhibitors: Avoid concomitant use. (7.1) ? P-gp inhibitors: Avoid concomitant use. (7.1) ? Strong and Moderate CYP3A Inducers: Avoid concomitant use. (7.1) ? Certain CYP3A Substrates: Avoid concomitant use with CYP3A substrates, where minimal concentration changes can cause reduced efficacy. (7.2) ? Hormonal contraceptives: Avoid concomitant use. (7.2) --------------------------USE IN SPECIFIC POPULATIONS--------------------- ? Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDA approved-patient labeling. Revised: 11/2023 FULL PRESCRIBING INFORMATION: CONTENTS*

CONTRAINDICATIONS--

 None

WARNINGS AND PRECAUTIONS=

 Central Nervous System (CNS) Effects: Can cause CNS adverse reactions including dizziness, ataxia, and cognitive impairment. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity. (5.1) ? Interstitial Lung Disease (ILD)/Pneumonitis: Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. (5.2) ? Hepatotoxicity: Monitor liver function tests every 2 weeks during the first month of treatment, and as clinically indicated thereafter. Based on severity, withhold and then resume at same or reduced dose, or permanently discontinue. (5.3) ? Myalgia with Creatine Phosphokinase (CPK) Elevation: Monitor serum CPK levels during treatment in patients reporting unexplained muscle pain, tenderness, or weakness. Based on severity, withhold and resume at same or reduced dose upon improvement. (5.4) ? Hyperuricemia: Monitor serum uric acid levels prior to initiating and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold and resume at same or reduced dose, or permanently discontinue based on severity. (5.5) ? Skeletal Fractures: Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. (5.6) ? Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use an effective non-hormonal method of contraception. (5.7) ---------------------------

tenderness, or weakness. Based on severity, withhold and resume at same or reduced dose upon improvement. (5.4) ? Hyperuricemia: Monitor serum uric acid levels prior to initiating and periodically during treatment. Initiate treatment with urate-lowering medications as clinically indicated. Withhold and resume at same or reduced dose, or permanently discontinue based on severity. (5.5) ? Skeletal Fractures: Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures. (5.6) ? Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use an effective non-hormonal method of contraception. (5.7) -------------------------------ADVERSE REACTIONS------------------------------ The most common adverse reactions (=20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. ---------

---------------------DRUG INTERACTIONS------------------------------- ? Strong and Moderate CYP3A Inhibitors: Avoid concomitant use. (7.1) ? P-gp inhibitors: Avoid concomitant use. (7.1) ? Strong and Moderate CYP3A Inducers: Avoid concomitant use. (7.1) ? Certain CYP3A Substrates: Avoid concomitant use with CYP3A substrates, where minimal concentration changes can cause reduced efficacy. (7.2) ? Hormonal contraceptives: Avoid concomitant use. (7.2)

--------------------------USE IN SPECIFIC POPULATIONS--------------------- ? Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING I

PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Patient Information). Central Nervous System (CNS) Effects ? Advise patients to inform their healthcare provider if they experience new or worsening CNS symptoms. Instruct patients not to drive or operate hazardous machinery if they are experiencing CNS adverse reactions [see Warnings and Precautions (5.1)]. 16 Reference ID: 5277680 Interstitial Lung Disease (ILD)/Pneumonitis ? Advise patients to inform their healthcare provider if they experience new or worsening pulmonary symptoms indicative of ILD/pneumonitis [see Warnings and Precautions (5.2)]. Hepatotoxicity ? Advise patients of the need for laboratory tests to monitor liver function and to immediately report symptoms of hepatotoxicity [see Warnings and Precautions (5.3)]. Myalgia with Creatinine Phosphokinase Elevation ? Advise patients to inform their healthcare provider if they experience muscle pain [see Warnings and Precautions (5.4)]. Hyperuricemia ? Advise patients to inform their healthcare provider if they experience signs or symptoms associated with hyperuricemia [see Warnings and Precautions (5.5)]. Skeletal Fractures ? Inform patients that bone fractures have occurred in patients taking AUGTYRO and advise patients to report symptoms to their healthcare provider [see Warnings and Precautions (5.6)]. Embryo-Fetal Toxicity ? Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.7), Use in Specific Populations (8.1, 8.3)]. ? Advise females of reproductive potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months after the last dose, since AUGTYRO can render some hormonal contraceptives ineffective [see Drug Interactions (7.2)]. ? Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AUGTYRO and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. Lactation ? Advise females not to breastfeed during treatment with AUGTYRO and for 10 days after the last dose [see Use in Specific Populations (8.2)]. Drug Interactions ? Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)]. ? Advise patients to avoid grapefruit or grapefruit juice while taking AUGTYRO [see Drug Interactions (7)]. ? Advise patients that hormonal contraceptives can be ineffective while taking AUGTYRO [see Drug Interactions (7)]. 17 Reference ID: 5277680 Administration ? Advise patients to swallow AUGTYRO capsules whole with or without food [see Dosage and Administration (2.6), Pharmacokinetics (12.3)]. ? Instruct patients if they miss a dose, or vomit at any time after taking a dose of AUGTYRO, not to “make it up,” but take the next dose of AUGTYRO at the next scheduled time [see Dosage and Administration (2.6)]. For more information, go to www.AUGTYRO.com or call 1-877-284-8976.

Distributed by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713 AUGTYROTM is a trademark of Turning Point Therapeutics, Inc., a Bristol Myers Squibb company.

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Repotrectinib is an inhibitor of proto-oncogene tyrosine-protein kinase ROS1 (ROS1) and of the tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC. Fusion proteins that include ROS1 domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways leading to unconstrained cell proliferation. Repotrectinib exhibited anti-tumor activity in cultured cells expressing ROS1 fusions and mutations including SDC4-ROS1, SDC4-ROS1G2032R, CD74-ROS1, CD74-ROS1G2032R, CD74- ROS1D2033N, and CD74-ROS1L2026M . 12.2 Pharmacodynamics Repotrectinib exposure-response relationships and the time course of pharmacodynamic responses are not fully characterized. Cardiac Electrophysiology AUGTYRO does not cause a mean increase in the QTc interval > 20 milliseconds (ms) at 160 mg QD followed by 160 mg BID, the approved recommended dosage. 12.3 Pharmacokinetics The geometric mean (CV%) of repotrectinib steady state peak concentration (Cmax,ss) is 713 (32.5%) ng/mL and the area under the time concentration curve (AUC0-24h,ss) is 7210 (40.1%) ng•h/mL following the approved recommended twice daily dosage in patients with cancer. Repotrectinib Cmax and AUC0-inf increases approximately dose proportional (but less than linear with estimated slopes of 0.78 and 0.70, respectively) over the single dose range of 40 mg to 240 mg (0.25 to 1.5 times the approved recommended dosage). Steady state PK was time-dependent with an autoinduction of CYP3A4. Steady state is achieved within 14 days of daily administration of 160 mg. Absorption The geometric mean (CV%) absolute bioavailability of repotrectinib is 45.7% (19.6%). Peak repotrectinib concentration occurred at approximately 2 to 3 hours post a single oral dose of 40 mg to 240 mg (0.25 to 1.5 times the approved recommended dosage) under fasted conditions. Effect of Food No clinically significant differences in repotrectinib pharmacokinetics were observed in patients with cancer following administration of a high-fat meal (approximately 800-1000 calories, 50% fat). Distribution The geometric mean (CV%) apparent volume of distribution (Vz/F) was 432 L (55.9 %) in patients with cancer following a single 160 mg oral dose of AUGTYRO. AUGTYRO binding to plasma protein was 95.4% in vitro. The blood-to-plasma ratio was 0.56 in vitro. Elimination Repotrectinib elimination is time-dependent due to autoinduction of CYP3A4. 13 Reference ID: 5277680 The repotrectinib mean terminal half-life is approximately 50.6 h for patients with cancer following a single dose. The steady state repotrectinib terminal half-life is approximately 35.4 h for patients with cancer. The geometric mean (CV%) apparent oral clearance (CL/F) was 15.9 L/h (45.5%) in patients with cancer following a single 160 mg oral dose of AUGTYRO. Metabolism Repotrectinib is primarily metabolized by CYP3A4 followed by secondary glucuronidation. Excretion Following a single oral 160 mg dose of radiolabeled repotrectinib, 4.84% (0.56% as unchanged) was recovered in urine and 88.8% (50.6% unchanged) in feces. Specific Populations No clinically significant differences in the pharmacokinetics of repotrectinib were observed based on age (18 to 84 years), sex, race/ethnicity (Caucasian 54%, Asian 38%, Black 7%), mild to moderate renal impairment (eGFR 30 to < 90 mL/min), or mild hepatic impairment (total bilirubin >1 to 1.5 times ULN or AST > ULN). The effect of moderate (total bilirubin >1.5 to 3 times ULN with any AST) or severe (total bilirubin >3 x ULN with any AST) hepatic impairment, severe renal impairment, kidney failure (eGFR < 30 mL/min), or dialysis on repotrectinib pharmacokinetics is unknown or not fully characterized. Drug Interaction Studies Clinical Studies Strong CYP3A and P-gp inhibitors: Repotrectinib AUC0-inf increased by 5.9-fold and Cmax by 1.7- fold following concomitant use with itraconazole (strong CYP3A and P-gp inhibitor). Strong CYP3A and P-gp inducers: Repotrectinib AUC0-inf decreased by 92% and Cmax by 79% following concomitant use with rifampin (strong CYP3A and P-gp inducer). CYP3A substrates: Midazolam (CYP3A substrate AUC0-inf decreased by 69% and Cmax by 48% following concomitant use in subjects who were previously administered 160 mg repotrectinib once daily for 14 days followed by 160 mg twice daily for 7 days. In vitro Studies CYP Enzymes: Repotrectinib induces CYP3A4, CYP2B6, CYP2C8, CYP2C19, CYP2C9 and inhibits CYP3A4/5 (GI tract). Repotrectinib does not induce CYP1A2. Other Metabolic Pathways: Repotrectinib inhibits UGT1A1. Transporter Systems: Repotrectinib inhibits P-gp, BCRP, OATP1B1, and MATE2-K. Repotrectinib is a substrate for P-gp.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with repotrectinib were not conducted. 14 Reference ID: 527768

DRUG INTERACTIONS 7.1 Effects of Other Drugs on AUGTYRO Strong and Moderate CYP3A Inhibitors Avoid concomitant use with strong or moderate CYP3A inhibitors. Concomitant use of AUGTYRO with a strong or a moderate CYP3A inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Discontinue 9 Reference ID: 5277680 CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating AUGTYRO [see Clinical Pharmacology (12.3)]. P-gp Inhibitors Avoid concomitant use with P-gp inhibitors. Concomitant use of AUGTYRO with a P-gp inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO [see Clinical Pharmacology (12.3)]. Strong and Moderate CYP3A Inducers Avoid concomitant use with strong or moderate CYP3A inducers. Concomitant use of AUGTYRO with a strong or moderate CYP3A inducer may decrease repotrectinib plasma concentrations, which may decrease efficacy of AUGTYRO [see Clinical Pharmacology (12.3)]. 7.2 Effects of AUGTYRO on Other Drugs Certain CYP3A4 Substrates Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates, where minimal concentration changes can cause reduced efficacy. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling. Repotrectinib is a CYP3A4 inducer. Concomitant use of repotrectinib decreases the concentration of CYP3A4 substrates [see Clinical Pharmacology (12.3)], which can reduce the efficacy of these substrates. Contraceptives Repotrectinib is a CYP3A4 inducer, which can decrease progestin or estrogen exposure to an extent that could reduce the effectiveness of hormonal contraceptives. Avoid concomitant use of AUGTYRO with hormonal contraceptives [see Use in Specific Populations (8.1, 8.3)]. Advise females to use an effective nonhormonal contraceptive. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action [see Clinical Pharmacology (12.1)], AUGTYRO can cause fetal harm when administered to a pregnant woman. There are no available data on AUGTYRO use in pregnant women. Oral administration of repotrectinib to pregnant rats during the period of organogenesis resulted in fetal malformations at doses approximately 0.3 times the recommended dose of 160 mg twice daily based on BSA (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 Human Data 10 Reference ID: 5277680 Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK-mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis. Animal Data In an embryo-fetal development study, once daily oral administration of repotrectinib to pregnant rats during the period of organogenesis from gestation day 6 to 17 resulted in maternal effects of increased body weight and skin abrasions/ulcerations at doses =6 mg/kg, fetal malformations of malrotated hindlimbs and lower fetal body weights at doses =12 mg/kg [approximately 0.3 times the recommended dose of 160 mg twice daily based on BSA]. No embryolethality was observed. 8.2 Lactation Risk Summary There are no data on the presence of AUGTYRO in human milk or its effects on either the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children from AUGTYRO, advise a lactating woman to discontinue breastfeeding during treatment with AUGTYRO and for 10 days after the last dose. 8.3 Females and Males of Reproductive Potential AUGTYRO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify the pregnancy status of females of childbearing potential prior to initiating AUGTYRO [see Use in Specific Populations (8.1)]. Contraception AUGTYRO can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Females Advise females of childbearing potential to use effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the last dose. AUGTYRO can render some hormonal contraceptives ineffective [see Drug Interactions (7.2)]. Males Based on genotoxicity findings, advise male patients with female partners of childbearing potential to use effective contraception during treatment with AUGTYRO and for 4 months following the last dose [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of AUGTYRO in pediatric patients with ROS1-positive NSCLC has not been established. Juvenile Animal Data Daily oral administration of repotrectinib to juvenile rats for 8 weeks starting on postnatal day 12 (approximately equal to a human pediatric age of a newborn) resulted in toxicities similar to those observed in adult rats, though juvenile animals showed decreased body weight gain at doses =1 11 Reference ID: 5277680 mg/kg (approximately =0.04 times the human exposure based on AUC at the recommended clinical dose of 160 mg BID) and decreased femur lengths at 3 mg/kg (approximately 0.1 times the human exposure based on AUC at the recommended clinical dose of 160 mg BID). Decreased body weight gain and decreased femur lengths persisted following 4 weeks of recovery. 8.5 Geriatric Use Of the 351 patients who received AUGTYRO, 21% were 65 to 75 years old, and 7% were 75 years of age or older. There were no clinically meaningful differences in safety and efficacy between patients younger than 65 years of age and patients 65 years of age or older. 8.6 Renal Impairment The recommended dosage of AUGTYRO has not been established in patients with severe renal impairment or kidney failure (eGFR-MDRD <30 mL/min) and patients on dialysis [see Clinical Pharmacology (12.3)]. No dosage modification is recommended for patients with mild or moderate renal impairment (eGFR-MDRD 30 to 90 mL/min). 8.7 Hepatic Impairment The recommended dosage of AUGTYRO has not been established in patients with moderate (total bilirubin >1.5 to 3 times upper limit of normal [ULN] with any AST) or severe (total bilirubin >3 times ULN with any AST) hepatic impairment [see Clinical Pharmacology (12.3)]. No dosage modification is recommended fo

11 DESCRIPTION Repotrectinib is a kinase inhibitor. The molecular formula for repotrectinib is C18H18FN5O2 and the molecular weight is 355.37 Daltons. The chemical name is (3R,11S)-6-Fluoro-3,11-dimethyl10-oxa-2,13,17,18,21-pentaazatetracyclo[13.5.2.04,9.018,22]docosa-1(21),4,6,8,15(22),16,19- heptaen-14