Drug Interactions between adagrasib and efavirenz / lamivudine / tenofovir disoproxil

GENERALLY AVOID: Adagrasib can cause concentration-dependent, prolongation of the QT interval. Coadministration with other agents that can prolong the QT interval may increase the risk of ventricular arrhythmias including torsade de pointes and sudden death. According to cardiac electrophysiology data provided by the manufacturer, the mean (90% CI) QTcF change from baseline was 18 ms at the mean steady-state maximum concentration (Cmax,ss) after administration of adagrasib 600 mg twice daily. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of adagrasib with other drugs that can prolong the QT interval should generally be avoided. If concomitant use cannot be avoided, monitor electrocardiogram and electrolytes prior to starting adagrasib and during concomitant use. Withhold adagrasib if the QTc interval is greater than 500 ms or the change from baseline is greater than 60 ms until QTc interval is less than 481 ms or QT interval returns to baseline, then adagrasib may be resumed at the next lower dose level. Adagrasib should be permanently discontinued if torsade de pointes, polymorphic ventricular tachycardia or signs or symptoms of serious or life-threatening arrhythmia occur. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

MONITOR: Coadministration of efavirenz with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Efavirenz has been associated with hepatotoxicity during postmarketing use. Among reported cases of hepatic failure, a few occurred in patients with no preexisting hepatic disease or other identifiable risk factors.

MANAGEMENT: The risk of hepatic injury should be considered when efavirenz is used in combination with other agents that are potentially hepatotoxic (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; other HIV reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Monitoring of liver function tests should occur before and during treatment, especially in patients with underlying hepatic disease (including hepatitis B or C coinfection) or marked transaminase elevations. The benefit of continued therapy with efavirenz should be considered against the unknown risks of significant liver toxicity in patients who develop persistent elevations of serum transaminases greater than five times the upper limit of normal.

MONITOR: Coadministration of efavirenz with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Efavirenz has been associated with hepatotoxicity during postmarketing use. Among reported cases of hepatic failure, a few occurred in patients with no preexisting hepatic disease or other identifiable risk factors.

MANAGEMENT: The risk of hepatic injury should be considered when efavirenz is used in combination with other agents that are potentially hepatotoxic (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; other HIV reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Monitoring of liver function tests should occur before and during treatment, especially in patients with underlying hepatic disease (including hepatitis B or C coinfection) or marked transaminase elevations. The benefit of continued therapy with efavirenz should be considered against the unknown risks of significant liver toxicity in patients who develop persistent elevations of serum transaminases greater than five times the upper limit of normal.

MONITOR: Coadministration with adagrasib may increase the plasma concentrations of drugs that are metabolized by the CYP450 3A4, 2D6 or 2C9 enzymatic pathways or are substrates of the P-glycoprotein (P-gp) efflux membrane transporter. When adagrasib 400 mg twice daily (two-thirds the approved recommended dosage) was administered with midazolam (a sensitive CYP450 3A4 substrate) and dextromethorphan (a sensitive CYP450 2D6 substrate) in pharmacokinetic studies, midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 4.8- and 21-fold, respectively, while dextromethorphan Cmax and AUC increased by 1.9- and 1.8-fold, respectively. Adagrasib at the approved recommended dosage of 600 mg twice daily is predicted to increase midazolam Cmax by 3.1-fold and AUC by 31-fold; dextromethorphan Cmax by 1.7-fold and AUC by 2.4-fold; warfarin (a sensitive CYP450 2C9 substrate) Cmax by 1.1-fold and AUC by 2.9-fold; and digoxin (a P-gp substrate) Cmax by 1.9-fold and AUC by 1.5-fold. These results suggest that adagrasib is a potent inhibitor of CYP450 3A4 and may be a moderate inhibitor of CYP450 2D6 and 2C9 at the approved recommended dosage of 600 mg twice daily.

MANAGEMENT: Caution is advised when adagrasib is used concomitantly with drugs that are substrates of CYP450 3A4, CYP450 2D6, CYP450 2C9 and/or P-gp, particularly sensitive substrates or those with a narrow therapeutic range. Substitution for these medications is recommended when possible, or initiate with lower dosages and monitor patient clinical response/tolerance and titrate accordingly if coadministration is required. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration and for any dosage adjustments that may be required.