DRUG INTERACTIONS- (summary)

 See full prescribing information for clinically significant drug interactions with KRAZATI.

 • Strong CYP3A4 Inducers: Avoid concomitant use. (7.1) • Strong CYP3A4 Inhibitors: Avoid concomitant use until adagrasib concentrations have reached steady state.

 • Sensitive CYP3A4 Substrates: Avoid concomitant use with sensitive CYP3A4 substrates.

 • Sensitive CYP2C9 or CYP2D6 Substrates or P-gp Substrates: Avoid concomitant use with sensitive CYP2C9 or CYP2D6 substrates or P-gp substrates where minimal concentration changes may lead to serious adverse reactions.

DRUG INTERACTIONS-(details)

1. Effects of Other Drugs on KRAZATI Strong CYP3A4 Inducers-                               Avoid concomitant use of KRAZATI with strong CYP3A inducers. Adagrasib is a CYP3A4 substrate. Concomitant use of KRAZATI with a strong CYP3A inducer reduces adagrasib exposure  which may reduce the effectiveness of KRAZATI.

Strong CYP3A4 Inhibitors-                                                                                         Avoid concomitant use of KRAZATI with strong CYP3A inhibitors until adagrasib concentrations have reached steady state (after approximately 8 days). Adagrasib is a CYP3A4 substrate.

If adagrasib concentrations have not reached steady state, concomitant use of a strong CYP3A inhibitor will increase adagrasib concentrations,  which may increase the risk of KRAZATI adverse reactions.

2. Effects of KRAZATI on Other Drugs Sensitive CYP3A Substrates-                  Avoid concomitant use of KRAZATI with sensitive CYP3A substrates unless otherwise recommended in the Prescribing Information for these substrates.

Adagrasib is a CYP3A inhibitor. Concomitant use with KRAZATI increases exposure of CYP3A substrates , which may increase the risk of adverse reactions related to these substrates.

Sensitive CYP2C9 Substrates- Avoid concomitant use of KRAZATI with sensitive CYP2C9 substrates where minimal concentration changes may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information for these substrates.

Adagrasib is a CYP2C9 inhibitor. Concomitant use with KRAZATI increases exposure of CYP2C9 substrates , which may increase the risk of adverse reactions related to these substrates.

Sensitive CYP2D6 Substrates- Avoid concomitant use of KRAZATI with sensitive CYP2D6 substrates where minimal concentration changes may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information for these substrates.

Adagrasib is a CYP2D6 inhibitor. Concomitant use with KRAZATI increases exposure of CYP2D6 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates.

 P-gp Substrates Avoid concomitant use of KRAZATI with P-gp substrates where minimal concentration changes may lead to serious adverse reactions unless otherwise recommended in the Prescribing Information for these substrates.

Adagrasib is a P-gp inhibitor. Concomitant use with KRAZATI increases exposure of P-gp substrates , which may increase the risk of adverse reactions related to these substrates.

3. Drugs That Prolong QTc Interval -Avoid concomitant use of KRAZATI with other product(s) with a known potential to prolong the QTc interval.

If concomitant use cannot be avoided, monitor electrocardiogram and electrolytes prior to starting KRAZATI, during concomitant use, and as clinically indicated..

Withhold KRAZATI if the QTc interval is > 500 ms or the change from baseline is > 60 ms

 Adagrasib causes QTc interval prolongation.

Concomitant use of KRAZATI with other products that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including Torsade de pointes, other serious arrythmias, and sudden death.

 • Drugs That Prolong QT Interval: Avoid concomitant use with KRAZATI.

BRIEF SUMMARY

ADAGRASIB-(Dec 2022)

Indn- to treat KRAS  G12Cmuated   mutated locally   advanced non-small lung cancer in adults  who  have received at least one prior therapy

Comp- Tablets: 200 mg. Recommended dosage: 600 mg orally twice daily.   Swallow tablets whole with or without food.

ADR-  The most common (= 25%) adverse reactions were nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, and decreased appetite.

CI- None.

 WARNINGS AND PRECAUTIONS-

• Gastrointestinal Adverse Reactions: Monitor patients for diarrhea, nausea and vomiting and provide supportive care as needed. Withhold, reduce the dose or permanently discontinue based on severity.

 • QTc Interval Prolongation: Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval.

Pat inform-

Gastrointestinal Adverse Reactions -  Advise patients that  can cause severe gastrointestinal adverse reactions and to contact their healthcare provider for signs or symptoms of severe or persistent gastrointestinal adverse reactions..

QTc Interval Prolongation- Advise patients that  can cause QTc interval prolongation and to contact their healthcare provider for signs or symptoms of arrhythmias..

Hepatotoxicity-  Advise patients that  can cause hepatotoxicity and to immediately contact their healthcare provider for signs or symptoms of liver dysfunction.

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

U.S.  APPROVED DRUGS DURING 2022                                        

Serial No 32

Name-        KRAZATI

Active  Ingredient -  Adagrasib

Pharmacological clssificiation-        To treat KRAS  G12Cmuated   mutated locally                                                               advanced non-small lung cancer in adults                                                                    who  have received at least one prior therapy                                                                                                                                                                                                                                                                                             Date of Approved-         12/12/2022                                        

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use                          KRAZATI safely and effectively.                                                                                     See full prescribing information for KRAZATI. KRAZATI™ (adagrasib) tablets, for oral use

Initial U.S. Approval: 2022

INDICATIONS AND USAGE

KRAZATI is an inhibitor of the RAS GTPase family indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA approved test, who have received at least one prior systemic therapy.

 This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).

ADVERSE REACTIONS-

 • The most common (= 25%) adverse reactions were nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, and decreased appetite.

 • The most common Grade 3 or 4 (= 2%) laboratory abnormalities were decreased lymphocytes, decreased hemoglobin, increased alanine aminotransferase, increased aspartate aminotransferase, hypokalemia, hyponatremia, increased lipase, decreased leukocytes, decreased neutrophils and increased alkaline phosphatase.

 CONTRAINDICATIONS-

None.

 WARNINGS AND PRECAUTIONS-

• Gastrointestinal Adverse Reactions: Monitor patients for diarrhea, nausea and vomiting and provide supportive care as needed. Withhold, reduce the dose or permanently discontinue based on severity.

 • QTc Interval Prolongation: Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval.

Monitor ECG and electrolytes in patients at risk, and in patients taking medications known to prolong the QT interval. Withhold, reduce the dose, or permanently discontinue based on severity.

 • Hepatotoxicity: Monitor liver laboratory tests prior to the start of KRAZATI and monthly for 3 months after and as clinically indicated. Reduce the dose, withhold, or permanently discontinue based on severity. 

Interstitial Lung Disease / Pneumonitis: Monitor for new or worsening respiratory symptoms. Withhold KRAZATI for suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified.

____________________DRUG INTERACTIONS____________________ See full prescribing information for clinically significant drug interactions with KRAZATI. (7) • Strong CYP3A4 Inducers: Avoid concomitant use. (7.1) • Strong CYP3A4 Inhibitors: Avoid concomitant use until adagrasib concentrations have reached steady state. (7.1) • Sensitive CYP3A4 Substrates: Avoid concomitant use with sensitive CYP3A4 substrates. (7.2) • Sensitive CYP2C9 or CYP2D6 Substrates or P-gp Substrates: Avoid concomitant use with sensitive CYP2C9 or CYP2D6 substrates or P-gp substrates where minimal concentration changes may lead to serious adverse reactions. (7.2) • Drugs That Prolong QT Interval: Avoid concomitant use with KRAZATI.

(7.3) USE IN SPECIFIC POPULATIONS _______________ Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient la

DOSAGE AND ADMINISTRATION-

• Recommended dosage: 600 mg orally twice daily.

 • Swallow tablets whole with or without food.

 DOSAGE FORMS AND STRENGTHS -

Tablets: 200 mg.

PATIENT COUNSELING INFORMATION -

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Gastrointestinal Adverse Reactions -                                                                           Advise patients that KRAZATI can cause severe gastrointestinal adverse reactions and to contact their healthcare provider for signs or symptoms of severe or persistent gastrointestinal adverse reactions..

QTc Interval Prolongation-                                                                                         Advise patients that KRAZATI can cause QTc interval prolongation and to contact their healthcare provider for signs or symptoms of arrhythmias..

Hepatotoxicity-                                                                                                               Advise patients that KRAZATI can cause hepatotoxicity and to immediately contact their healthcare provider for signs or symptoms of liver dysfunction.

Interstitial Lung Disease (ILD)/Pneumonitis-                                                                 Advise patients that KRAZATI can cause ILD / pneumonitis and to contact their healthcare provider immediately for new or worsening respiratory symptoms [see

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

Missed Dose-                                                                                                                    If a dose of KRAZATI is missed by greater than 4 hours, resume dosing at the next scheduled time [see Dosage and Administration (2.2)]. Lactation Advise women not to breastfeed during treatment with KRAZATI and for 1 week after the last dose [see

Use in Specific Populations -                                                                                            Infertility- Inform patients that KRAZATI may cause infertility [see Use in Specific Populations (8.3)] KRAZATI (adagrasib) 

 Manufactured for: Mirati Therapeutics, Inc. 3545 Cray Court San Diego, CA 92121, U.S.A. © 2022 Mirati Therapeutics, Inc. All Rights Reserved

CLINICAL PHARMACOLOGY

1. Mechanism of Action- Adagrasib is an irreversible inhibitor of KRAS G12C that covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive state that prevents downstream signaling without affecting wild-type KRAS protein.

Adagrasib inhibits tumor cell growth and viability in cells harboring KRAS G12C mutations and results in tumor regression in KRAS G12C-mutated tumor xenograft models with minimal off-target activity.

2. Pharmacodynamics- Adagrasib exposure-response relationships and the time course of pharmacodynamic response are unknown.

Cardiac Electrophysiology- Adagrasib increased QTc in a concentration-dependent manner.

Based on the concentrationQTcF relationship, the mean (90% CI) QTcF change from baseline (?QTcF) was 18 (15, 21) ms at the mean steady-state maximum concentration (Cmax,ss) in patients after administration of adagrasib 600 mg twice daily [see Warnings and Precautions (5.2)]. Reference ID: 5095255 13

3. The pharmacokinetics- of adagrasib were studied in healthy subjects and in patients with KRAS G12C-mutated NSCLC and are presented as mean (percent coefficient of variation) unless otherwise specified. Adagrasib AUC and Cmax increase dose proportionally over the dose range of 400 mg to 600 mg (0.67 to 1 times the approved recommended dose).

Adagrasib steady-state was reached within 8 days following administration of the approved recommended dosage and accumulation was approximately 6-fold. Absorption The median (min, max) Tmax of adagrasib is approximately 6 (6, 12) hours.

Effect of Food -No clinically significant differences in the pharmacokinetics of adagrasib were observed following administration of a high-fat and high-calorie meal (containing approximately 900 to 1000 calories, 50% from fat).

Distribution- The apparent volume of distribution of adagrasib is 942 L (57%). Human plasma protein binding of adagrasib is approximately 98% in vitro.

Elimination- The adagrasib terminal elimination half-life is 23 hours (16%) and the apparent oral clearance (CL/F) is 37 L/h (54%) in patients.

Metabolism- Adagrasib is metabolized primarily by CYP3A4 following single dose administration. Adagrasib inhibits its own CYP3A4 metabolism following multiple dosing to steady-state which permits CYP2C8, CYP1A2, CYP2B6, CYP2C9, and CYP2D6 to contribute to its metabolism at steadystate.

Excretion- Following a single oral dose of radiolabeled adagrasib, approximately 75% of the dose was recovered in feces (14% as unchanged) and 4.5% recovered in urine (2% as unchanged).

Specific Populations- No clinically significant differences in the pharmacokinetics of adagrasib based on age (19 to 89 years), sex, race (White, Black or African American, or Asian), body weight (36 to 139 kg), ECOG PS (0, 1), or tumor burden. No clinically significant differences in the pharmacokinetics of adagrasib are expected in patients with mild to severe renal impairment (CLcr 15 to < 90 mL/min estimated by Cockcroft-Gault equation) or in patients with mild to severe hepatic impairment (Child-Pugh classes A to C). Reference ID: 5095255 14

Drug Interaction Studies- Clinical Studies and Model-Informed Approaches The following table describes the effect of other drugs on the pharmacokinetics of adagrasib.

 Effect of Other Drugs on Adagrasib Concomitant Drug Adagrasib Dosage Changes in Cmax or AUC of Adagrasib Cmax % Decrease AUC % Decrease Rifampin (a strong CYP3A inducer) 600 mg single dose 88% 95% 600 mg multiple doses > 61%a > 66%a Cmax = maximum plasma concentration; AUC = area under the plasma concentration-time curve a Predicted changes in Cmax or AUC of adagrasib Strong CYP3A Inhibitors:

Adagrasib Cmax increased by 2.4-fold and AUC increased by 4-fold following concomitant use of a single dose of 200 mg (0.33 times the approved recommended dose) with itraconazole (a strong CYP3A inhibitor).

No clinically significant differences in the pharmacokinetics of adagrasib at steady state were predicted when used concomitantly with itraconazole.

No clinically significant differences in the pharmacokinetics of adagrasib were predicted or observed when used concomitantly with efavirenz (a moderate CYP3A inducer), pantoprazole (a proton pump inhibitor), or rosuvastatin (a BCRP/OATP substrate).

 USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary -                                                                                          There are no available data on the use of KRAZATI in pregnant women.

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-                                                                                                                 There are no data on the presence of adagrasib or its metabolites in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with KRAZATI and for 1 week after the last dose.

3. Females and Males of Reproductive Potential Infertility -Based on findings from animal studies, KRAZATI may impair fertility in females and males of reproductive potential .

4. Pediatric Use- The safety and effectiveness of KRAZATI has not been established in pediatric patients.

5. Geriatric Use- Of 116 patients who received adagrasib 600 mg orally twice daily in KRYSTAL-1, 49% (57 patients) were = 65 years of age. No overall differences in safety or effectiveness were observed between older and younger patients.