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Adagrasib 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 Adagrasib based on severity.
Adagrasib 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. Adagrasib causes concentrationdependent increases in the QTc interval . Avoid concomitant use of Adagrasib with other products with a known potential to prolong the QTc interval. Avoid use of Adagrasib in patients with congenital long QT syndrome and in patients with concurrent QTc prolongation. Monitor ECGs and electrolytes prior to starting Adagrasib, 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 Adagrasib depending on severity.
Adagrasib 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 Adagrasib 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 Adagrasib based on severity.
Adagrasib 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 Adagrasib. Withhold Adagrasib in patients with suspected ILD/pneumonitis and permanently discontinue Adagrasib if no other potential causes of ILD/pneumonitis are identified.
FDA,2022.12
