Adagrasib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.[2]
Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
Black Box Warning
|
{{{blackBoxWarningTitle}}}
See full prescribing information for complete Boxed Warning.
{{{blackBoxWarningBody}}}
|
Overview
Adagrasib is an {{{drugClass}}} that is FDA approved for the treatment of KRAZATI is 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 [see DOSAGE AND ADMINISTRATION (2.1)], 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) [see CLINICAL STUDIES (14)]. Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Gastrointestinal Adverse Reactions QTc Interval Prolongation Hepatotoxicity Interstitial Lung Disease (ILD)/Pneumonitis.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Tablets: 200 mg, oval shaped, white to off-white, immediate release film coated tablets with "200" on one side and stylized "M" on the opposite side.
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of KRAZATI has not been established in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Contraindications
None
Warnings
|
{{{blackBoxWarningTitle}}}
See full prescribing information for complete Boxed Warning.
{{{blackBoxWarningBody}}}
|
5.1 Gastrointestinal Adverse Reactions KRAZATI can cause severe gastrointestinal adverse reactions.
In the pooled safety population [see ADVERSE REACTIONS (6.1)], serious gastrointestinal adverse reactions observed were gastrointestinal bleeding in 3.8% including 0.8% Grade 3 or 4, gastrointestinal obstruction in 1.6% including 1.4% Grade 3 or 4, colitis in 0.5% including 0.3% Grade 3, ileus in 0.5%, and stenosis in 0.3%. In addition, nausea, diarrhea, or vomiting occurred in 89% of 366 patients, including 9% Grade 3. Nausea, diarrhea, or vomiting led to dosage interruption or dose reduction in 29% of patients and permanent discontinuation of adagrasib in 0.3%.
Monitor and manage patients using supportive care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Withhold, reduce the dose, or permanently discontinue KRAZATI based on severity [see DOSAGE AND ADMINISTRATION (2.3)].
5.2 QTc Interval Prolongation KRAZATI can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death.
In the pooled safety population [see ADVERSE REACTIONS (6.1)], 6% of 366 patients with at least one post-baseline electrocardiogram (ECG) assessment had an average QTc ≥ 501 ms and 11% of patients had an increase from baseline of QTc > 60 msec. KRAZATI causes concentration-dependent increases in the QTc interval [see CLINICAL PHARMACOLOGY (12.2)].
Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval. [see DRUG INTERACTIONS (7.3) and CLINICAL PHARMACOLOGY (12.2)]. Avoid use of KRAZATI in patients with congenital long QT syndrome and in patients with concurrent QTc prolongation.
Monitor ECGs and electrolytes prior to starting KRAZATI, during concomitant use, and as clinically indicated in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and in patients who are unable to avoid concomitant medications that are known to prolong the QT interval. Withhold, reduce the dose, or permanently discontinue KRAZATI depending on severity [see DOSAGE AND ADMINISTRATION (2.3)].
5.3 Hepatotoxicity KRAZATI can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis.
In the pooled safety population of 366 patients [see ADVERSE REACTIONS (6.1)], drug-induced liver injury was reported in 0.3% of patients, including 0.3% Grade 3. A total of 32% of patients who received adagrasib had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 5% were Grade 3 and 0.5% were Grade 4. The median time to first onset of increased ALT/AST was 3 weeks (range: 0.1 to 48). Overall hepatotoxicity occurred in 37%, and 7% were Grade 3 or 4. Hepatotoxicity leading to dose interruption or reduction occurred in 12% of patients. Adagrasib was discontinued due to hepatotoxicity in 0.5% of patients.
Monitor liver laboratory tests (AST, ALT, alkaline phosphatase and total bilirubin) prior to the start of KRAZATI and monthly for 3 months or as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Reduce the dose, withhold, or permanently discontinue KRAZATI based on severity [see DOSAGE AND ADMINISTRATION (2.3) and ADVERSE REACTIONS (6.1)].
5.4 Interstitial Lung Disease /Pneumonitis KRAZATI can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal.
In the pooled safety population [see ADVERSE REACTIONS (6.1)], ILD/pneumonitis occurred in 4.1% of patients, 1.4% were Grade 3 or 4, and one case was fatal. The median time to first onset for ILD/pneumonitis was 12 weeks (range: 5 to 31 weeks). Adagrasib was discontinued due to ILD/pneumonitis in 0.8% of patients.
Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever) during treatment with KRAZATI. Withhold KRAZATI in patients with suspected ILD/pneumonitis and permanently discontinue KRAZATI if no other potential causes of ILD/pneumonitis are identified [see DOSAGE AND ADMINISTRATION (2.3)].
Adverse Reactions
Clinical Trials Experience
5.1 Gastrointestinal Adverse Reactions KRAZATI can cause severe gastrointestinal adverse reactions.
In the pooled safety population, serious gastrointestinal adverse reactions observed were gastrointestinal bleeding in 3.8% including 0.8% Grade 3 or 4, gastrointestinal obstruction in 1.6% including 1.4% Grade 3 or 4, colitis in 0.5% including 0.3% Grade 3, ileus in 0.5%, and stenosis in 0.3%. In addition, nausea, diarrhea, or vomiting occurred in 89% of 366 patients, including 9% Grade 3. Nausea, diarrhea, or vomiting led to dosage interruption or dose reduction in 29% of patients and permanent discontinuation of adagrasib in 0.3%.
Monitor and manage patients using supportive care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Withhold, reduce the dose, or permanently discontinue KRAZATI based on severity.
5.2 QTc Interval Prolongation KRAZATI can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death.
In the pooled safety population, 6% of 366 patients with at least one post-baseline electrocardiogram (ECG) assessment had an average QTc ≥ 501 ms and 11% of patients had an increase from baseline of QTc > 60 msec. KRAZATI causes concentration-dependent increases in the QTc interval.
Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval. Avoid use of KRAZATI in patients with congenital long QT syndrome and in patients with concurrent QTc prolongation.
Monitor ECGs and electrolytes prior to starting KRAZATI, during concomitant use, and as clinically indicated in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and in patients who are unable to avoid concomitant medications that are known to prolong the QT interval. Withhold, reduce the dose, or permanently discontinue KRAZATI depending on severity.
5.3 Hepatotoxicity KRAZATI can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis.
In the pooled safety population of 366 patients , drug-induced liver injury was reported in 0.3% of patients, including 0.3% Grade 3. A total of 32% of patients who received adagrasib had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 5% were Grade 3 and 0.5% were Grade 4. The median time to first onset of increased ALT/AST was 3 weeks (range: 0.1 to 48). Overall hepatotoxicity occurred in 37%, and 7% were Grade 3 or 4. Hepatotoxicity leading to dose interruption or reduction occurred in 12% of patients. Adagrasib was discontinued due to hepatotoxicity in 0.5% of patients.
Monitor liver laboratory tests (AST, ALT, alkaline phosphatase and total bilirubin) prior to the start of KRAZATI and monthly for 3 months or as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Reduce the dose, withhold, or permanently discontinue KRAZATI based on severity.
5.4 Interstitial Lung Disease /Pneumonitis KRAZATI can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal.
In the pooled safety population , ILD/pneumonitis occurred in 4.1% of patients, 1.4% were Grade 3 or 4, and one case was fatal. The median time to first onset for ILD/pneumonitis was 12 weeks (range: 5 to 31 weeks). Adagrasib was discontinued due to ILD/pneumonitis in 0.8% of patients.
Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever) during treatment with KRAZATI. Withhold KRAZATI in patients with suspected ILD/pneumonitis and permanently discontinue KRAZATI if no other potential causes of ILD/pneumonitis are identified.
Postmarketing Experience
There is limited information regarding Adagrasib Postmarketing Experience in the drug label.
Drug Interactions
7.1 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 [see CLINICAL PHARMACOLOGY (12.3)], 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.
7.2 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, 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 [see CLINICAL PHARMACOLOGY (12.3)], which may increase the risk of adverse reactions related to these substrates.
7.3 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 [see WARNINGS AND PRECAUTIONS (5.2)]. Withhold KRAZATI if the QTc interval is > 500 ms or the change from baseline is > 60 ms.
Adagrasib causes QTc interval prolongation [see CLINICAL PHARMACOLOGY (12.2)]. 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.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): There are no available data on the use of KRAZATI in pregnant women. In animal reproduction studies, oral administration of adagrasib to pregnant rats and rabbits during the period of organogenesis did not cause adverse development effects or embryo-fetal lethality at exposures below the human exposure at the recommended dose of 600 mg twice daily (see DATA).
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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Adagrasib in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Adagrasib during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Adagrasib in women who are nursing.
Pediatric Use
The safety and effectiveness of KRAZATI has not been established in pediatric patients.
Geriatic 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.
Gender
There is no FDA guidance on the use of Adagrasib with respect to specific gender populations.
Race
There is no FDA guidance on the use of Adagrasib with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Adagrasib in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Adagrasib in patients with hepatic impairment.
Females of Reproductive Potential and Males
Based on findings from animal studies, KRAZATI may impair fertility in females and males of reproductive potential.
Immunocompromised Patients
There is no FDA guidance one the use of Adagrasib in patients who are immunocompromised.
Administration and Monitoring
Administration
2.1 Patient Selection Select patients for treatment of locally advanced or metastatic NSCLC with KRAZATI based on the presence of KRAS G12C mutation in plasma or tumor specimens [see CLINICAL STUDIES (14)]. If no mutation is detected in a plasma specimen, test tumor tissue.
Information on FDA-approved tests for the detection of a KRAS G12C mutation is available at: https://www.fda.gov/CompanionDiagnostics
2.2 Recommended Dosage The recommended dosage of KRAZATI is 600 mg orally twice daily until disease progression or unacceptable toxicity.
Take KRAZATI at the same time every day with or without food [see CLINICAL PHARMACOLOGY (12.3)]. Swallow tablets whole. Do not chew, crush or split tablets.
If vomiting occurs after taking KRAZATI, do not take an additional dose. Resume dosing at the next scheduled time.
If a dose is inadvertently missed, it should be skipped if greater than 4 hours have elapsed from the expected dosing time. Resume dosing at the next scheduled time.
2.3 Dosage Modifications for Adverse Reactions Recommended dose reductions for adverse reactions are outlined in Table 1. If adverse reactions occur, a maximum of two dose reductions are permitted. Permanently discontinue KRAZATI in patients who are unable to tolerate 600 mg once daily.
Table 1: Recommended KRAZATI Dosage Reductions for Adverse Reactions Dose Reduction Dosage First dose reduction 400 mg twice daily Second dose reduction 600 mg once daily The recommended dosage modifications for adverse reactions are provided in Table 2.
Table 2: Recommended KRAZATI Dosage Modifications for Adverse Reactions Adverse reaction Severity* Dosage Modification ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal
- Grading defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0
Nausea or vomiting despite appropriate supportive care (including anti-emetic therapy) [see WARNINGS AND PRECAUTIONS (5.1)] Grade 3 or 4 Withhold KRAZATI until recovery to ≤ Grade 1 or return to baseline. Resume KRAZATI at the next lower dose level. Diarrhea despite appropriate supportive care (including anti-diarrheal therapy) [see WARNINGS AND PRECAUTIONS (5.1)] Grade 3 or 4 Withhold KRAZATI until recovery to ≤ Grade 1 or return to baseline. Resume KRAZATI at the next lower dose level. QTc Interval Prolongation [see WARNINGS AND PRECAUTIONS (5.2)] QTc absolute value greater than 500 ms or Greater than an increase of 60 ms from baseline Withhold KRAZATI until QTc interval less than 481 ms or return to baseline. Resume KRAZATI at the next lower dose level. Torsade de pointes, polymorphic ventricular tachycardia or signs or symptoms of serious or life-threatening arrhythmia Permanently discontinue KRAZATI. Hepatotoxicity [see WARNINGS AND PRECAUTIONS (5.3)] Grade 2 AST or ALT Decrease KRAZATI to the next lower dose level. Grade 3 or 4 AST or ALT Withhold KRAZATI until recovery to ≤ Grade 1 or return to baseline. Resume KRAZATI at the next lower dose level. AST or ALT > 3 × ULN with total bilirubin > 2 × ULN in the absence of alternative causes Permanently discontinue KRAZATI. Interstitial Lung Disease / Pneumonitis [see WARNINGS AND PRECAUTIONS (5.4)] Any Grade Withhold KRAZATI if ILD/pneumonitis is suspected. Permanently discontinue KRAZATI if ILD/pneumonitis is confirmed. Other Adverse Reactions [see ADVERSE REACTIONS (6.1)] Grade 3 or 4 Withhold KRAZATI until ≤ Grade 1 or return to baseline. Resume KRAZATI at the next lower dose level.
Monitoring
5.1 Gastrointestinal Adverse Reactions
Monitor and manage patients using supportive care, including antidiarrheals, antiemetics, or fluid replacement, as indicated. Withhold, reduce the dose, or permanently discontinue KRAZATI based on severity [see DOSAGE AND ADMINISTRATION (2.3)].
5.2 QTc Interval Prolongation Monitor ECGs and electrolytes prior to starting KRAZATI, during concomitant use, and as clinically indicated in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, and in patients who are unable to avoid concomitant medications that are known to prolong the QT interval. Withhold, reduce the dose, or permanently discontinue KRAZATI depending on severity [see DOSAGE AND ADMINISTRATION (2.3)].
5.3 Hepatotoxicity Monitor liver laboratory tests (AST, ALT, alkaline phosphatase and total bilirubin) prior to the start of KRAZATI and monthly for 3 months or as clinically indicated, with more frequent testing in patients who develop transaminase elevations. Reduce the dose, withhold, or permanently discontinue KRAZATI based on severity [see DOSAGE AND ADMINISTRATION (2.3) and ADVERSE REACTIONS (6.1)].
5.4 Interstitial Lung Disease /Pneumonitis Monitor patients for new or worsening respiratory symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever) during treatment with KRAZATI. Withhold KRAZATI in patients with suspected ILD/pneumonitis and permanently discontinue KRAZATI if no other potential causes of ILD/pneumonitis are identified [see DOSAGE AND ADMINISTRATION (2.3)].
IV Compatibility
There is limited information regarding the compatibility of Adagrasib and IV administrations.
Overdosage
There is limited information regarding Adagrasib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Adagrasib Pharmacology in the drug label.
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.
Structure
There is limited information regarding Adagrasib Structure in the drug label.
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 concentration-QTcF relationship, the mean (90% CI) QTcF change from baseline (ΔQTcF) was 18 (15, 21) ms at the mean steady-state maximum concentration (Cmax,ss) in patients after administration of adagrasib 600 mg twice daily
Pharmacokinetics
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 steady-state.
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).
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
The following table describes the effect of other drugs on the pharmacokinetics of adagrasib.
Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with adagrasib.
Adagrasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not genotoxic in an in vitro chromosomal aberration assay or an in vivo micronucleus assay in rats.
Fertility studies were not conducted with adagrasib. In toxicology studies of up to 13-weeks in duration in rats, oral administration of adagrasib induced phospholipidosis which increased vacuolation in female reproductive organs, including vacuolation in ovaries (corpora lutea, macrophage or interstitial cells) and uterus (glandular epithelium), and atrophy with mucification of the vaginal mucosa at doses ≥ 150 mg/kg (approximately equal to or greater than the human exposure at the recommended dose based on area under the curve [AUC]). These findings reversed after cessation of dosing in the 28-day study but in the 13-week study, pigmented macrophage aggregates were observed in the ovaries of female rats after the recovery period. In a 28-day repeat-dose toxicology study, oral administration of adagrasib to male rats induced atrophy and epithelial vacuolation of the prostate gland and seminal vesicles at 300 mg/kg (approximately 1.6 times the human exposure at the recommended dose based on AUC). These findings resolved after cessation of treatment.
13.2 Animal Toxicology and/or Pharmacology Phospholipidosis (vacuolation and/or presence of foamy macrophages) was observed in multiple organs (e.g., lung, trachea, heart, skeletal, ovaries, uterus, adrenal gland, kidney, liver, lymph nodes, spleen, thymus, and thyroid in rats; and heart and lung in dogs) after repeated oral administration of adagrasib in rats and dogs. In toxicology studies of up to 13-week duration in rats, phospholipidosis was observed at doses ≥ 150 mg/kg (approximately ≥ 2 times the human exposure at the recommended dose based on AUC). In a dog 28-day toxicity study, this effect was observed at 25 mg/kg (approximately equal to the human exposure at the recommended dose based on AUC). The extent of vacuolization and the presence of foamy macrophages were more prominent in the rat compared to dogs, and evidence of reversibility after cessation of treatment was noted for most organs. The significance of this finding in humans in unknown.
Clinical Studies
The efficacy of adagrasib was evaluated in KRYSTAL-1 (NCT03785249), a multicenter, single-arm, open-label expansion cohort study. Eligible patients were required to have locally advanced or metastatic KRAS G12C-mutated NSCLC who previously received treatment with a platinum-based regimen and an immune checkpoint inhibitor, an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1, and at least one measurable lesion as defined by Response Evaluation criteria in Solid Tumors (RECIST v1.1). Identification of a KRAS G12C mutation was prospectively determined by local testing using tissue specimens. Patients received adagrasib 600 mg orally twice daily until unacceptable toxicity or disease progression. Tumor assessments were performed every 6 weeks. The major efficacy outcome measures were confirmed objective response rate (ORR) and duration of response (DOR) as evaluated by blinded independent central review (BICR) according to RECIST v1.1.
In the efficacy population, KRAS G12C mutation status was determined by prospective local testing using tumor tissue specimens. Of the 112 patients with KRAS G12C mutation, tissue samples from 88% (98/112) patients were tested retrospectively using the QIAGEN therascreen KRAS RGQ PCR Kit. While 89% (87/98) of patients were positive for KRAS G12C mutation, 11% (11/98) did not have a KRAS G12C mutation identified. In addition, plasma samples from 63% (71/112) patients were tested retrospectively using Agilent Resolution ctDx FIRST assay. While 66% (47/71) of patients were positive for KRAS G12C mutation, 34% (24/71) did not have a KRAS G12C mutation identified.
A total of 112 patients had at least one measurable lesion at baseline as assessed by BICR according to RECIST v1.1.
The baseline demographic and disease characteristics in the efficacy population were: median age 64 years (range: 25 to 89), 55% female, 83% White, 8% were Black or African American, 4% Asian, 4% race not reported, 0.9% American Indian or Alaska Native, 16% Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 and 83% ECOG PS 1. Tumor histology was 97% adenocarcinoma and 89% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1 to 7); 43% received 1 prior line, 35% received 2 prior lines, 10% received 3 prior lines and 12% received 4 or more prior lines, 98% received both prior platinum and prior anti-PD-1/PD-L1 therapy. Sites of extra-thoracic disease included bone 42%, brain 30%, adrenals 21%, and liver 21%.
How Supplied
KRAZATI (adagrasib) tablets, 200 mg, oval shaped, white to off-white, immediate release, film coated tablets with "200" on one side and stylized "M" on the other side.
KRAZATI (adagrasib) tablets are packaged in high-density polyethylene, white opaque, square bottles with desiccant and polypropylene, white, child resistant closures with a tamper-proof heat induction seal.
NDC 80739-812-12: 200 mg, bottle containing 120 tablets.
NDC 80739-812-18: 200 mg, bottle containing 180 tablets.
Storage
Store tablets at room temperature, 20°C to 25°C (68°F to 77°F). Temperature excursions between 15°C and 30°C (59°F to 86°F) are permitted [see USP Controlled Room Temperature].
Images
Drug Images
{{#ask: Page Name::Adagrasib |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}
Package and Label Display Panel
{{#ask: Label Page::Adagrasib |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}
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 [see WARNINGS AND PRECAUTIONS (5.1)].
QTc Interval Prolongation
Advise patients that KRAZATI can cause QTc interval prolongation and to contact their healthcare provider for signs or symptoms of arrhythmias [see WARNINGS AND PRECAUTIONS (5.2)].
Hepatotoxicity
Advise patients that KRAZATI can cause hepatotoxicity and to immediately contact their healthcare provider for signs or symptoms of liver dysfunction [see WARNINGS AND PRECAUTIONS (5.3)].
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 WARNINGS AND PRECAUTIONS (5.4)].
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 (7.1)].
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 (8.2)].
Infertility
Inform patients that KRAZATI may cause infertility [see USE IN SPECIFIC POPULATIONS (8.3)]
Precautions with Alcohol
Alcohol-Adagrasib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
Krazati
Look-Alike Drug Names
There is limited information regarding Adagrasib Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.