ADAGRASIB Drug Interactions: What You Need to Know

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. ( 7.2 )
• Sensitive CYP2C9 or CYP2D6 Substrates or P-gp Substrates : Avoid concomitant use with sensitive CYP2C9 or CYP2D6 substrates or P-gp substrates where minimal concentration changes may lead to serious adverse reactions. ( 7.2 )
• Drugs That Prolong QT Interval : Avoid concomitant use with KRAZATI. ( 7.3 )

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , 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, <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>, 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>. Withhold KRAZATI if the QTc interval is &gt; 500 ms or the change from baseline is &gt; 60 ms <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span>. Adagrasib causes QTc interval prolongation <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span>. 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>.

None. None. ( 4 )

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. Correct electrolyte abnormalities. Withhold, reduce the dose, or permanently discontinue based on severity. ( 2.3 , 5.2 )
• Hepatotoxicity: Monitor liver laboratory tests prior to the start of KRAZATI and monthly for 3 months after and as clinically indicated. Reduce the dose, withhold, or permanently discontinue based on severity. ( 2.3 , 5.3 )
• Interstitial Lung Disease (ILD) / Pneumonitis: Monitor for new or worsening respiratory symptoms. Withhold KRAZATI for suspected ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis are identified. ( 2.3 , 5.4 )

5.1 Gastrointestinal Adverse Reactions KRAZATI can cause severe gastrointestinal adverse reactions. In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> , who received single-agent KRAZATI, 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%. In patients who received KRAZATI in combination with cetuximab <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> , serious gastrointestinal adverse reactions included gastrointestinal bleeding in 8.5% including 1.1% Grade 3 or 4, gastrointestinal obstruction in 5.3% including 5.3% Grade 3 or 4, colitis in 1.1% including 1.1% Grade 3 and ileus in 1.1%. In addition, nausea, diarrhea, or vomiting occurred in 92% of 94 patients, including 6% Grade 3. Nausea, diarrhea, or vomiting led to adagrasib dose interruption or dose reduction in 23% of patients. 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span>.

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> who received single-agent KRAZATI , 6% of 366 patients with at least one post-baseline electrocardiogram (ECG) assessment had an average QTc ≥ 501 msec and 11% of patients had an increase from baseline of QTc &gt; 60 msec. KRAZATI causes concentration-dependent increases in the QTc interval <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . In patients who received KRAZATI in combination with cetuximab <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> , 5% of 93 patients with at least one post-baseline electrocardiogram (ECG) assessment had an average QTc ≥ 501 msec and 16% of patients had an increase from baseline of QTc &gt; 60 msec. Avoid concomitant use of KRAZATI with other products with a known potential to prolong the QTc interval <span class="opacity-50 text-xs">[see Drug Interactions (7.3) and Clinical Pharmacology (12.2) ]</span>. Avoid use of KRAZATI in patients with congenital long QT syndrome and in patients with concurrent QTc prolongation. Monitor ECGs and electrolytes , particularly potassium and magnesium, 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. Correct electrolyte abnormalities. Withhold, reduce the dose, or permanently discontinue KRAZATI depending on severity <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> who received single-agent KRAZATI , 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. In patients who received KRAZATI in combination with cetuximab <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> , 29% had increased alanine aminotransferase (ALT)/increased aspartate aminotransferase (AST); 5% were Grade 3 and 1.1% were Grade 4. The median time to first onset of increased ALT/AST was 4 weeks (range: 0.1 to 27). Overall hepatotoxicity occurred in 38%, and 10% were Grade 3 or 4. Hepatotoxicity leading to adagrasib dose interruption or reduction occurred in 12% 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) and Adverse Reactions (6.1) ]</span>.

5.4 Interstitial Lung Disease / Pneumonitis KRAZATI can cause interstitial lung disease (ILD)/pneumonitis, which can be fatal. In the pooled safety population <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> who received single-agent KRAZATI , 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. In patients who received KRAZATI in combination with cetuximab <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> , Grade 1 ILD/pneumonitis occurred in 1.1% of patients. The time to first onset for ILD/pneumonitis was 38 weeks. 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span>.