Adagrasib (Monograph)

Brand name: Krazati
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Mar 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent;irreversible inhibitor of Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C.

Uses for Adagrasib

Non-small Cell Lung Cancer (NSCLC)

Treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC who have received ≥1 prior systemic therapy (designated an orphan drug by FDA for this use).

Accelerated approval based on objective response rate and duration of response; continued approval contingent upon verification and description of clinical benefit in confirmatory trial(s).

Adagrasib Dosage and Administration

General

Pretreatment Screening

• Confirm the presence of KRAS G12C mutation in plasma or tumor specimens by an FDA-approved diagnostic test prior to initiating therapy.

• Monitor liver function tests (AST, ALT, alkaline phosphatase, and total bilirubin) prior to initiating therapy.

• Monitor ECGs and electrolytes prior to initiating therapy.

Patient Monitoring

• Monitor ECGs and electrolytes during concomitant use of adagrasib with other drugs known to prolong QT_c when such concomitant use cannot be avoided, and as clinically indicated in patients with congestive heart failure, bradyarrhythmias, or electrolyte abnormalities.

• Monitor liver function tests (AST, ALT, alkaline phosphatase, and total bilirubin) monthly for 3 months during treatment or as clinically indicated, with more frequent testing in patients who develop transaminase elevations.

• Monitor patients for new or worsening respiratory symptoms indicative of interstitial lung disease (ILD)/pneumonitis during therapy.

• Monitor patients for GI adverse effects (diarrhea, nausea, and vomiting) during therapy.

Administration

Oral Administration

Administer orally twice daily. Administer at the same time every day, with or without food.

Swallow tablets whole; do not chew, crush, or split tablets.

If vomiting occurs after taking a dose, do not take an additional dose; resume dosing at the next scheduled time.

If a dose is missed, skip the dose if >4 hours have elapsed from the expected dosing time; resume dosing at the next scheduled time.

Dosage

Adults

Non-small Cell Lung Cancer

Oral

600 mg twice daily; continue until disease progression or unacceptable toxicity occurs.

<C> Dosage Modification for Toxicity

If adverse effects occur during adagrasib therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance may be necessary.

Consult Table 1 for recommended dosage reductions for adverse reactions. Maximum of 2 dosage reductions allowed if an adverse reaction occurs; permanently discontinue in patients unable to tolerate 600 mg once daily.

Consult Table 2 for recommended dosage adjustments for adverse reactions based on severity.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Related/similar drugs

Opdivo, methotrexate, Keytruda, pembrolizumab, Avastin, cisplatin, Tagrisso

Cautions for Adagrasib

Contraindications

• None.

Warnings/Precautions

Adverse GI Reactions

Severe adverse GI reactions reported, such as GI bleeding (including grade 3 or 4 events), GI obstruction (including grade 3 or 4 events), colitis (including grade 3 events), ileus, and stenosis.

Nausea, diarrhea, or vomiting reported commonly, including grade 3 events.

Monitor for GI adverse reactions. Provide supportive care (including antidiarrheals, antiemetics, or fluid replacement) as indicated. Withhold, reduce dosage, or permanently discontinue adagrasib based on severity.

QTc Interval Prolongation

Prolongation of the QT interval corrected for rate (QT_c) reported; can increase risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death.

QT_c interval increases are concentration-dependent.

Avoid adagrasib in patients with congenital long QT syndrome and in those with concurrent QT_c prolongation, as well as in patients taking other products known to prolong the QT_c interval.

Monitor ECGs and electrolytes prior to adagrasib initiation, and when concomitant use with other drugs known to prolong the QT interval cannot be avoided, and as clinically indicated in patients with CHF, bradyarrhythmias, or electrolyte abnormalities.

If QT_c prolongation occurs, withhold, reduce dosage, or permanently discontinue adagrasib based on severity.

Hepatotoxicity

Hepatotoxicity, which may result in drug-induced liver injury and hepatitis, reported.

Increased ALT/AST reported, including grade 3 and 4 events.

Monitor liver function tests (AST, ALT, alkaline phosphatase and total bilirubin) prior to adagrasib initiation and monthly for 3 months during treatment or as clinically indicated; more frequent testing recommended in patients who develop transaminase elevations.

Interstitial Lung Disease/Pneumonitis

Interstitial lung disease (ILD)/pneumonitis, including fatal cases, reported.

Monitor for new or worsening respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever) during therapy.

Withhold therapy if ILD/pneumonitis suspected; permanently discontinue adagrasib if no other potential causes identified.

Specific Populations

Pregnancy

No available human data on adagrasib use during pregnancy. In animal reproduction studies, no adverse development effects or embryo-fetal lethality observed at exposures below the human exposure at the recommended dose of 600 mg twice daily.

Lactation

Unknown whether adagrasib (or its metabolites) is distributed into human milk, or affects milk production or the nursing infant.

Advise women not to breast-feed during treatment with adagrasib and for 1 week after the last dose.

Females and Males of Reproductive Potential

Based on animal studies, may impair fertility in females and males of reproductive potential.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in efficacy or safety between geriatric patients (≥65 years of age) and younger adults.

Hepatic Impairment

No clinically important pharmacokinetic differences expected in patients with mild to severe hepatic impairment (Child-Pugh classes A to C).

Renal Impairment

No clinically important pharmacokinetic differences expected in patients with mild to severe renal impairment (Cl_cr 15 to <90 mL/minute).

Common Adverse Effects

Most common adverse reactions in patients with NSCLC (≥25%): nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, decreased appetite.

Most common grade 3 or 4 laboratory abnormalities (≥2%): decreased lymphocytes, decreased hemoglobin, increased ALT, increased AST, hypokalemia, hyponatremia, increased lipase, decreased leukocytes, decreased neutrophils, increased alkaline phosphatase.

Drug Interactions

Substrate of CYP isoenzyme 3A4. Inhibitor of CYP isoenzymes 3A, 2C9, and 2D6, and the efflux transporter P-glycoprotein (P-gp).

May inhibit CYP isoenzyme 2B6, multidrug and toxin extrusion (MATE)-1, and MATE-2K; may be a substrate of breast cancer resistance protein (BCRP).

Drugs Affecting Hepatic Microsomal Enzymes

Strong CYP3A4 Inducers

Concomitant use reduces adagrasib exposure; may consequently reduce effectiveness.

Avoid concomitant use.

Strong CYP3A4 Inhibitors

Concomitant use may increase adagrasib concentrations if the concentrations have not reached steady state; this may increase risk of adverse reactions.

Avoid concomitant use until adagrasib concentrations have reached steady state (after approximately 8 days).

Drugs Metabolized by Hepatic Microsomal Enzymes

Sensitive CYP3A Substrates

Concomitant use increases exposure of the CYP3A substrate; may consequently increase risk of adverse reactions related to the substrate.

Avoid concomitant use unless otherwise recommended in the prescribing information for the substrate.

Sensitive CYP2C9 Substrates

Concomitant use increases exposure of the CYP2C9 substrate; may consequently increase risk of adverse reactions related to the substrate.

Avoid concomitant use where minimal concentration changes may lead to serious adverse reactions, unless otherwise recommended in the prescribing information for the substrate.

Sensitive CYP2D6 Substrates

Concomitant use increases exposure of the CYP2D6 substrate; may consequently increase risk of adverse reactions related to the substrate.

Avoid concomitant use where minimal concentration changes may lead to serious adverse reactions, unless otherwise recommended in the prescribing information for the substrate.

Drugs Affected by the P-glycoprotein Transport System

Concomitant use increases exposure of the P-gp substrate; may consequently increase risk of adverse reactions related to the substrate.

Avoid concomitant use where minimal concentration changes may lead to serious adverse reactions, unless otherwise recommended in the prescribing information for the substrate.

Drugs that Prolong the QTc Interval

Concomitant use with other drugs that prolong QT_c may result in a greater increase in QT_c interval and associated adverse reactions (e.g., torsade de pointes, other serious arrythmias, sudden death).

Avoid concomitant use with other drugs known to prolong the QT_c interval. If concomitant use unavoidable, monitor ECG and electrolytes prior to adagrasib initiation, during concomitant use, and as clinically indicated. Withhold adagrasib if QT_c interval >500 or if change from baseline >60; refer to Table 2 in the Dosage section for more information.

Specific Drugs

Adagrasib Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations and AUC increase proportionally over dose range of 400–600 mg (0.67–1 times the approved recommended dosage).

Steady-state reached within 8 days following administration of the approved recommended dosage; accumulation approximately 6-fold.

Median time to peak plasma concentration approximately 6 hours.

Food

No clinically important differences in adagrasib pharmacokinetics observed following administration of a high-fat, high-calorie meal (approximately 900–1000 calories, 50% from fat).

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

Approximately 98%.

Elimination

Metabolism

Primarily metabolized by CYP3A4. Following multiple dosing to steady-state, adagrasib inhibits its own CYP3A4 metabolism, permitting CYP isoenzymes 2C8, 1A2, 2B6, 2C9, and 2D6 to contribute to metabolism.

Elimination Route

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

Half-life

23 hours.

Special Populations

No clinically important differences in adagrasib pharmacokinetics observed based on age (19–89 years), sex, race (White, Black or African American, or Asian), body weight (36–139 kg), Eastern Cooperative Oncology Group Performance Status (0, 1), or tumor burden.

Stability

Storage

Oral

Tablets

20–25ºC (excursions permitted between 15–30ºC).

Actions

• Irreversible inhibitor of KRAS G12C; belongs to the RAS GTPase family.

• Forms a covalent bond with the mutant cysteine in KRAS G12C, locking the protein in an inactive state that prevents downstream signaling; wild-type KRAS not affected.

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

Advice to Patients

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

• Advise patients that adagrasib can cause severe GI adverse reactions (e.g., severe nausea, diarrhea, and/or vomiting; GI bleeding or obstruction; colitis; stenosis) and to contact their clinician if signs or symptoms of severe or persistent GI adverse reactions occur.

• Advise patients that adagrasib can cause QT_c prolongation and to contact their clinician if signs or symptoms of arrhythmias (e.g., dizziness, lightheadedness, abnormal heartbeats) occur.

• Advise patients that adagrasib can cause hepatotoxicity and to contact their clinician immediately if they develop signs or symptoms of liver dysfunction (e.g., jaundice, dark or "tea-colored" urine, light-colored stools, loss of appetite, pain in the right side of the abdomen).

• Advise patients that adagrasib can cause interstitial lung disease/pneumonitis and to contact their clinician immediately if new or worsening respiratory symptoms (e.g., dyspnea, cough, fever) occur.

• Advise patient to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Instruct patients that if they miss a dose of adagrasib by more than 4 hours, they should resume dosing at the next scheduled time.

• Advise women to inform their clinician if they are or plan to become pregnant or breast-feed. Advise women not to breast-feed during treatment with adagrasib and for 1 week after the last dose.

• Advise male and female patients of reproductive potential that adagrasib may cause infertility.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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