Summary

 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], 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

 Advise females to use an effective nonhormonal contraceptive.

BRIEF SUMMARY

REPOTRECTINIB-(Nov 2023)

Indn-   to treat Rosi- Non-small small cell lung cancer

Comp-    Capsules: 40 mg   Recommended Dosage: 160 mg orally once daily for 14 days, then increase to 160 mg twice daily, with or without food

ADR-    The most common adverse reactions (=20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness

CI-    None

WARNINGS -

 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.

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

Pat Inform- 

 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 [s

Interstitial Lung Disease (ILD)/Pneumonitis-                                                                Advise patients to inform their healthcare provider if they experience new or worsening pulmonary symptoms indicative of ILD/pneumonitis

===============================================================

U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 49

Name-          AUGTYRO

Active ingedient-       Repotrectinib            

Indication              to treat Rosi- Non-small 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)

ADVERSE REACTIONS-

 The most common adverse reactions (=20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness.

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.

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.

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.

 Myalgia with Creatine Phosphokinase (CPK) Elevation:

Monitor serum tenderness, or weakness. Based on severity, withhold and resume at same or reduced dose upon improvement.

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.

 Skeletal Fractures:                                                                                                      Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of fractures.

 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.

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 

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 [s

Interstitial Lung Disease (ILD)/Pneumonitis-

 Advise patients to inform their healthcare provider if they experience new or worsening pulmonary symptoms indicative of ILD/pneumonitis

 Hepatotoxicity -                                                                                                                  Advise patients of the need for laboratory tests to monitor liver function and to immediately report symptoms of hepatotoxicity

 Myalgia with Creatinine Phosphokinase Elevation-                                                          Advise patients to inform their healthcare provider if they experience muscle pain

 Hyperuricemia-                                                                                                                    Advise patients to inform their healthcare provider if they experience signs or symptoms associated with hyperuricemia

 Skeletal Fractures-                                                                                                          Inform patients that bone fractures have occurred in patients taking AUGTYRO and advise patients to report symptoms to their healthcare provider

 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

 Use in Specific Populations-                                                                                     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

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

 Lactation-                                                                                                                  Advise females not to breastfeed during treatment with AUGTYRO and for 10 days after the last dose

. Drug Interactions-                                                                                                   Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products

 Advise patients to avoid grapefruit or grapefruit juice while taking AUGTYRO

 Advise patients that hormonal contraceptives can be ineffective while taking AUGTYRO

 Administration-                                                                                                           Advise patients to swallow AUGTYRO capsules whole with or without food

 Pharmacokinetics-                                                                                                          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

. 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

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.

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.

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.

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.

Elimination-   Repotrectinib elimination is time-dependent due to autoinduction of CYP3A4 .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.

 USE IN SPECIFIC POPULATIONS-

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,

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 

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

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.

3 Females and Males of Reproductive Potential-                                                   AUGTYRO can cause fetal harm when administered to a pregnant woman

 Pregnancy Testing-                                                                                                           Verify the pregnancy status of females of childbearing potential prior to initiating AUGTYRO 

 Contraception-                                                                                                           AUGTYRO can cause embryo-fetal harm when administered to a pregnant woman

 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

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)].

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

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

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 [

No dosage modification is recommended for patients with mild or moderate renal impairment (eGFR-MDRD 30 to 90 mL/min).

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

No dosage modification is recommended for patients with mild (total bilirubin >1 to 1.5 times ULN or AST > ULN) hepatic impairment.