General MedicationsORALHigh Alert

KRAZATI

ADAGRASIB

Standard Dose

2 DOSAGE AND ADMINISTRATION • Recommended dosage as a single agent for NSCLC and in combination with cetuximab for CRC: 600 mg orally twice daily. ( 2.2 ) • Swallow tablets whole with or without food. ( 2.2 ) 2.1 Patient Selection Non-Small Cell Lung Cancer 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 (14.1) ] . If no mutation is detected in a plasma specimen, test tumor tissue. Colorectal Cancer Select patients for treatment of locally advanced or metastatic CRC with KRAZATI based on the presence of KRAS G12C mutation in tumor specimens [see Clinical Studies (14.2) ] . 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 as a single agent or in combination with cetuximab is 600 mg orally twice daily until disease progression or unacceptable toxicity. Refer to the cetuximab prescribing information for cetuximab dosage information [see Clinical Studies (14.2) ] . 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 for use of KRAZATI as a single agent or in combination with cetuximab 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 Refer to the cetuximab prescribing information for dose modifications for adverse reactions associated with cetuximab. When KRAZATI is administered in combination with cetuximab, withhold or permanently discontinue cetuximab when KRAZATI is withheld or permanently discontinued. Treatment with KRAZATI as a single agent may be continued if cetuximab is permanently discontinued. [see Clinical Pharmacology (12.1) , Clinical Studies (14.2) ] . The recommended dosage modifications for adverse reactions are provided in Table 2. Table 2: Recommended KRAZATI Dosage Modifications for Adverse Reactions ALT = alanine aminotransferase; AST = aspartate aminotransferase; ILD = Interstitial Lung Disease; ULN = upper limit of normal Adverse Reaction Severity Grading defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Dosage Modification When KRAZATI is administered in combination with cetuximab, withhold or permanently discontinue treatment with cetuximab when withholding or permanently discontinuing treatment with KRAZATI. 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.

Max Dose

See official label

Primary Use

1 INDICATIONS AND USAGE KRAZATI is an inhibitor of the RAS GTPase family indicated for: Non-small cell lung cancer (NSCLC)* • As a single agent, for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy.

Summary

Continued approval for these indications may be contingent upon verification and description of a clinical benefit in confirmatory trials. ( 1.1 , 1.2 ) 1.1 KRAS G12C-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer KRAZATI, as a single-agent, 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.

Structured Monograph

Clinical summary

Indications and usage 1 INDICATIONS AND USAGE KRAZATI is an inhibitor of the RAS GTPase family indicated for: Non-small cell lung cancer (NSCLC)* • As a single agent, for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy. ( 1.1 ) Colorectal cancer (CRC)* • In combination with cetuximab, for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic CRC, as determined by an FDA-approved test, who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. ( 1.2 ) *These indications are approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for these indications may be contingent upon verification and description of a clinical benefit in confirmatory trials. ( 1.1 , 1.2 ) 1.1 KRAS G12C-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer KRAZATI, as a single-agent, 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 (14.1) ]. Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial. 1.2 KRAS G12C-Mutated Locally Advanced or Metastatic Colorectal Cancer KRAZATI in combination with cetuximab is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC), as determined by an FDA-approved test [see Dosage and Administration (2.1) ] , who have received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This indication is approved under accelerated approval based on ORR and DOR [see Clinical Studies (14.2) ] . Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial. Dosage and administration 2 DOSAGE AND ADMINISTRATION • Recommended dosage as a single agent for NSCLC and in combination with cetuximab for CRC: 600 mg orally twice daily. ( 2.2 ) • Swallow tablets whole with or without food. ( 2.2 ) 2.1 Patient Selection Non-Small Cell Lung Cancer 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 (14.1) ] . If no mutation is detected in a plasma specimen, test tumor tissue. Colorectal Cancer Select patients for treatment of locally advanced or metastatic CRC with KRAZATI based on the presence of KRAS G12C mutation in tumor specimens [see Clinical Studies (14.2) ] . 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 as a single agent or in combination with cetuximab is 600 mg orally twice daily until disease progression or unacceptable toxicity. Refer to the cetuximab prescribing information for cetuximab dosage information [see Clinical Studies (14.2) ] . 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 for use of KRAZATI as a single agent or in combination with cetuximab 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 Refer to the cetuximab prescribing information for dose modifications for adverse reactions associated with cetuximab. When KRAZATI is administered in combination with cetuximab, withhold or permanently discontinue cetuximab when KRAZATI is withheld or permanently discontinued. Treatment with KRAZATI as a single agent may be continued if cetuximab is permanently discontinued. [see Clinical Pharmacology (12.1) , Clinical Studies (14.2) ] . The recommended dosage modifications for adverse reactions are provided in Table 2. Table 2: Recommended KRAZATI D

Monitoring

• 5 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.
• ( 2.3 , 5.1 ) • QTc Interval Prolongation: Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval.
• Monitor ECG and electrolytes particularly potassium and magnesium, in patients at risk, and in patients taking medications known to prolong the QT interval.

Interaction Notes

• 7 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.