KRAZATI

KRAZATI- adagrasib tablet, coated
Mirati Therapeutics, Inc

1 INDICATIONS AND USAGE

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).

2 DOSAGE AND 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 2AST or ALT	Decrease KRAZATI to the next lower dose level.
	Grade 3 or 4AST 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.

3 DOSAGE FORMS AND STRENGTHS

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.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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)].