Adagrasib is an irreversible inhibitor of the RAS GTPase family and KRAS G12C. It is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer, as determined by an FDA-approved test, who have received at least one prior systemic therapy. Adagrasib can cause interstitial lung disease (ILD)/pneumonitis, which may be fatal, and QT prolongation. Gastrointestinal toxicities are common; monitor for these reactions and manage with supportive care, fluid replacement, and an interruption of therapy, dose reduction, or discontinuation of therapy depending on the severity.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Moderate
-Administer routine antiemetic prophylaxis prior to treatment.
Route-Specific Administration
Oral Administration
-Adagrasib may be taken with or without food.
-Swallow tablets whole; do not chew, crush, or split tablets.
-If a patient vomits, do not administer an additional dose; resume therapy at the next scheduled time.
-If a dose is missed by more than 4 hours, skip that dose; resume therapy at the next scheduled time.
Serious mental status changes were reported in 2.6% of NSCLC patients who received adagrasib in a single-arm phase 1-1b trial.
Severe gastrointestinal toxicity was observed in patients with NSCLC and other solid tumors who received adagrasib in a pooled safety population (n = 366) including GI bleeding (3.8%; grade 3 or 4, 0.8%), GI obstruction (1.6%; grade 3 or 4, 1.4%), colitis (0.5%; grade 3, 0.3%), ileus (0.5%), and stenosis (0.3%). Nausea (69% to 70%; grade 3 or 4, 4.3%), diarrhea (69% to 70%; grade 3 or 4, 0.9%), or vomiting (56% to 57%; grade 3 or 4, 0.9%) occurred in most patients treated with adagrasib and resulted in an interruption of therapy or dose reduction in 29% of patients and permanent discontinuation in 0.3% of patients. Monitor patients for GI toxicity and use supportive care including antidiarrheals, antiemetics, and fluid replacement as indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary based on the severity of GI toxicity. Mild (grade 1 or 2) constipation (22%) and abdominal pain (21%) were additionally reported in NSCLC patients who received adagrasib in a single-arm phase 1-1b trial.
Decreased appetite/anorexia was observed in 29% to 30% (grade 3 or 4, 4.3%) of patients with NSCLC and other solid tumors who received adagrasib.
Adagrasib causes concentration-dependent QT prolongation. In a pooled safety analysis, of patients with NSCLC and other solid tumors who received adagrasib and had at least 1 post-baseline ECG (n = 366), 6% had an average QTc of 501 msec or greater, while 11% had an increase from baseline of more than 60 msec. The mean change in QTcF from baseline was 18 msec (90% CI, 15 msec to 21 msec) at the mean steady-state maximum concentration (Cmax) following administration of adagrasib 600 mg PO twice daily. In patients with NSCLC who received adagrasib 600 mg PO twice daily in a single-arm, phase 1-1B trial, 20% developed a prolonged QT interval (grade 3 or 4, 6%). Avoid the use of adagrasib in patients taking other medications with a known risk of QT prolongation. Additionally, avoid the use of adagrasib in patients with congenital long QT syndrome and in patients with baseline QT prolongation. Monitor ECGs and electrolytes prior to starting adagrasib therapy, during treatment, and as clinically indicated in patients with congestive heart failure, bradycardia, AV block, hypomagnesemia, hypokalemia, hypocalcemia, and in patients unable to avoid concurrent use of medications that prolong the QT interval. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity of QT prolongation.
Hepatotoxicity occurred in 37% (grade 3 or 4, 7% to 10%) of patients treated with adagrasib in patients with NSCLC and other solid tumors who received adagrasib, including mixed liver injury, elevated hepatic enzymes, hyperbilirubinemia, and increased conjugated bilirubin; grade 3 drug-induced liver injury was reported in 0.3% of patients. Transaminitis occurred in 32% (grade 3 or 4, 4.2% to 5.5%) of these patients, with a median time to first onset of 3 weeks; grade 3 or 4 increases in alkaline phosphatase were reported in 2% of patients. Hepatotoxicity led to an interruption of therapy or dose reduction in 12% of these patients and discontinuation of therapy in 0.5% of patients. In patients with NSCLC who received adagrasib, increased ALT was reported in 46% (grade 3 or 4, 5%) of patients and increased AST in 52% (grade 3 or 4, 6%) of patients. Monitor liver function tests at baseline and then monthly for 3 months or as clinically indicated; monitor more frequently in patients who develop transaminitis. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity of transaminitis or hyperbilirubinemia.
Pneumonitis/interstitial lung disease (ILD) occurred in 4.1% (grade 3 or 4, 1.4%) of patients with NSCLC and other solid tumors who received adagrasib in a pooled safety population (n = 366); one case was fatal. The median time to first onset of ILD/pneumonitis was 12 weeks (range: 5 to 31 weeks). Monitor patients for new or worsening respiratory symptoms including fever, cough, or dyspnea. Immediately interrupt adagrasib therapy in patients with new or worsening respiratory symptoms and permanently discontinue therapy if no other potential causes are identified. Dyspnea occurred in 26% to 35% (grade 3 or 4, 10%) and cough in 24% (grade 3 or 4, 0.9%) of patients who received adagrasib in clinical trials.
Fatigue occurred in 55% to 59% of patients with NSCLC and other solid tumors who received adagrasib in clinical trials (grade 3 or 4, 7%).
Mild (grade 1 or 2) edema occurred in 30% to 32% of patients with NSCLC and other solid tumors who received adagrasib in clinical trials.
Musculoskeletal pain occurred in 38% to 41% of patients with NSCLC and other solid tumors who received adagrasib in clinical trials (grade 3 or 4, 7%). Severe cases of muscle weakness occurred in 3.4% of patients with NSCLC who received adagrasib.
Increased lipase (2.5%) was among the most common grade 3 or 4 laboratory abnormalities in patients with NSCLC and other solid tumors who received adagrasib in a pooled safety population (n = 366); it occurred in 35% (grade 3 or 4, 1.8%) of patients with NSCLC who received adagrasib in a single-arm, phase 1-1b study (n = 116). Hyperamylasemia and increased lipase each resulted in an interruption of therapy in at least 2% of NSCLC treated with adagrasib.
Renal impairment occurred in 33% of patients with NSCLC and other solid tumors who received adagrasib in a pooled safety population (n = 366). In patients with NSCLC, 36% of patients developed renal impairment, including acute renal failure and increased serum creatinine; grade 3 or 4 renal impairment (renal failure) occurred in 6% of NSCLC patients. Mild (grade 1 or 2) increases in creatinine occurred in 50% of NSCLC patients who received adagrasib.
Dizziness occurred in 23% of patients with NSCLC who received adagrasib in a single-arm, phase 1-1b study (n = 116) (grade 3 or 4, 0.9%).
Infection occurred in NSCLC patients who received adagrasib in a single-arm, phase 1-1b study (n = 116), including pneumonia (24%; grade 3 or 4, 17%); 5% of patients developed sepsis.
Hematologic abnormalities including lymphopenia, anemia, thrombocytopenia, leukopenia, and neutropenia occurred in patients with NSCLC and other solid tumors who received adagrasib in a pooled safety population (n = 366); decreases from baseline in lymphocytes (20%), hemoglobin (7%), leukocytes (2.5%), and neutrophils (2.3%) were among the most common grade 3 or 4 laboratory abnormalities in the overall population. A decrease from baseline in lymphocytes (64%; grade 3 or 4, 25%), hemoglobin (51%; grade 3 or 4, 8%), and platelets (27%) were reported in NSCLC patients who received adagrasib in a single-arm, phase 1-1b study (n = 116). Severe anemia was reported in 3.4% of patients with NSCLC.
Hypoalbuminemia was reported in patients treated with adagrasib. A decrease from baseline in albumin levels occurred in 50% (grade 3 or 4, 0.9%) of NSCLC patients who received adagrasib in a single-arm, phase 1-1b study (n = 116).
Electrolyte abnormalities including hypokalemia, hyponatremia, and hypomagnesemia occurred in patients with NSCLC and other solid tumors who received adagrasib in a pooled safety population (n = 366); hypokalemia (3.6%) and hyponatremia (3.4%) were among the most common grade 3 or 4 laboratory abnormalities in the overall population. A decrease from baseline in sodium levels (52% (grade 3 or 4, 8%), in magnesium levels (26%), and in potassium levels (26%; grade 3 or 4, 3.5%) were reported in NSCLC patients who received adagrasib in a single-arm, phase 1-1b study (n = 116).
Serious cases of hypoxia (4.3%), pleural effusion (4.3%), and respiratory failure (4.3%) were reported in NSCLC patients who received adagrasib in a single-arm phase 1-1b trial.
Serious cases of heart failure (3.4%) were reported in NSCLC patients who received adagrasib in a single-arm phase 1-1b trial.
Serious cases of hypotension (3.4%) were reported in NSCLC patients who received adagrasib in a single-arm phase 1-1b trial.
Serious cases of dehydration (2.6%) were reported in NSCLC patients who received adagrasib in a single-arm phase 1-1b trial.
Pulmonary embolism occurred in 2.6% of NSCLC patients who received adagrasib in a single-arm phase 1-1b trial.
Occurrences of bleeding including pulmonary hemorrhage occurred in 2.6% of NSCLC patients who received adagrasib in a single-arm phase 1-1b trial.
Serious cases of fever (3.4%) were reported in NSCLC patients who received adagrasib in a single-arm phase 1-1b trial.
Severe gastrointestinal toxicity, including GI bleeding, GI obstruction, colitis, ileus, and stenosis, was observed with adagrasib therapy in patients with NSCLC and other solid tumors in a pooled safety population (n = 366). Nausea, diarrhea, or vomiting occurred in most patients treated with adagrasib. Monitor patients for GI toxicity and use supportive care including antidiarrheals, antiemetics, and fluid replacement as indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary based on the severity of GI toxicity.
Adagrasib can cause QT prolongation which can increase the risk for ventricular tachyarrhythmias, such as torsade de pointes, or sudden death. Avoid the use of adagrasib in patients taking other medications with a known risk of QT prolongation. Additionally, avoid the use of adagrasib in patients with congenital long QT syndrome and in patients with baseline QT prolongation. Monitor ECGs and electrolytes prior to starting adagrasib therapy, during treatment, and as clinically indicated in patients with congestive heart failure, bradycardia, AV block, hypomagnesemia, hypokalemia, hypocalcemia, and in patients unable to avoid concurrent use of medications that prolong the QT interval. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity of QT prolongation. Use adagrasib with caution in patients with conditions that may increase the risk of QT prolongation including stress-related cardiomyopathy, myocardial infarction, stroke, or in patients receiving medications known to cause an electrolyte imbalance. Females, geriatric patients, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.
Hepatotoxicity, such as mixed liver injury, elevated hepatic enzymes, and hyperbilirubinemia, have been reported with adagrasib therapy; use adagrasib with caution in patients with a history of hepatic disease. While no dose adjustments are necessary for baseline Child-Pugh A, B, or C hepatic disease, adagrasib can cause hepatotoxicity, which may lead to drug-induced liver injury and hepatitis. Monitor liver function tests at baseline and then monthly for 3 months or as clinically indicated; monitor more frequently in patients who develop transaminitis. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity of transaminitis or hyperbilirubinemia.
Use adagrasib with caution in patients who have a history of pre-existing chronic lung disease (CLD); severe pneumonitis/interstitial lung disease has been reported in patients treated with adagrasib. Monitor patients for new or worsening respiratory symptoms including fever, cough, or dyspnea. Immediately interrupt adagrasib therapy in patients with new or worsening respiratory symptoms and permanently discontinue therapy if no other potential causes are identified.
There are no adequately controlled studies of adagrasib use during human pregnancy. In an embryofetal study, administration of adagrasib to pregnant rats during organogenesis at a dose level approximately twice the recommended dose based on body surface area (BSA) resulted in maternal toxicity (e.g., reduced body weight and food intake, as well as clinical signs leading to moribund condition and early termination) and lower fetal body weight. Skeletal malformations, including bent limbs, and skeletal variations, such as bent scapula, wavy ribs, and supernumerary short cervical ribs, were also observed and determined to be secondary to maternal toxicity and reduced fetal body weight. In a rabbit embryofetal study, administration of adagrasib during organogenesis at exposures approximately 0.11 times the human exposure based on AUC at the recommended dose of 600 mg twice daily resulted in lower fetal body weight and increased litter frequency of unossified sternebra; this skeletal variation was associated with maternal toxicities, including reduced mean body weight and decreased food consumption. Adagrasib did not cause adverse developmental effects and did not affect embryofetal survival in rabbits at this dose level.
Although there are no data regarding the effect of adagrasib on human fertility, male and female infertility has been observed in animal studies. Based on animal studies, adagrasib may impair fertility of individuals of reproductive potential.
Due to the potential for serious adverse reactions in nursing infants from adagrasib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. There are no data on the presence of adagrasib or its metabolites in human milk, the effects on the breastfed child or on milk production.
For the treatment of non-small cell lung cancer (NSCLC):
NOTE: Adagrasib is designated as an orphan drug by the FDA for the treatment of KRAS G12C mutation positive NSCLC.
-for the treatment of previously treated locally advanced or metastatic non-small cell lung cancer (NSCLC) with a KRAS G12C mutation:
NOTE: Select patients based on the presence of a KRAS G12C mutation in plasma or tumor specimens; 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 www.fda.gov/CompanionDiagnostics.
Oral dosage:
Adults: 600 mg PO twice daily until disease progression or unacceptable toxicity. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a multicenter, single-arm, phase 1-1b study (KRYSTAL-1), treatment with adagrasib resulted in an objective response rate of 43% (complete response, 0.9%) and a median duration of response of 8.5 months in patients with locally advanced or metastatic KRAS G12C-mutated NSCLC previously treated with a platinum-based regimen and an immune checkpoint inhibitor (n = 112). Fifty-eight percent of patients had a duration of response of at least 6 months.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities
-First dose reduction: 400 mg PO twice daily.
-Second dose reduction: 600 mg PO once daily.
-Discontinue adagrasib therapy in patients unable to tolerate 600 mg PO once daily.
Diarrhea
-Grade 3 or 4 diarrhea despite appropriate supportive care (including anti-diarrheal therapy): Hold adagrasib therapy. When diarrhea resolves to grade 1 or less or baseline, resume adagrasib therapy at the next lower dose level.
Interstitial Lung Disease (ILD)/Pneumonitis
-Any grade: Hold adagrasib therapy for suspected ILD/pneumonitis. Permanently discontinue adagrasib therapy if ILD/pneumonitis is confirmed.
Nausea/Vomiting
-Grade 3 or 4 nausea/vomiting despite appropriate supportive care (including anti-emetic therapy): Hold adagrasib therapy. When nausea/vomiting resolves to grade 1 or less or baseline, resume adagrasib therapy at the next lower dose level.
QT Prolongation
-Absolute QTc interval greater than 500 msec OR more than a 60 msec increase from baseline: Hold adagrasib therapy. When the absolute QTc interval returns to less than 481 msec or baseline, resume adagrasib therapy at the next lower dose level.
-Torsade de pointes, polymorphic ventricular tachycardia, or signs or symptoms of serious or life-threatening arrhythmia: Permanently discontinue adagrasib therapy.
Other Adverse Reaction
-Grade 3 or 4: Hold adagrasib therapy. When toxicity resolves to grade 1 or less or baseline, resume adagrasib therapy at the next lower dose level.
Maximum Dosage Limits:
-Adults
600 mg PO twice daily.
-Geriatric
600 mg PO twice daily.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment
-Mild, Moderate, or Severe Hepatic Impairment (Child-Pugh A, B, or C): Dosage adjustments are not necessary.
Treatment-Related Hepatic Impairment
-Grade 2 increase in AST or ALT: Reduce the dose of adagrasib to the next lower dose level.
-Grade 3 or 4 increase in AST or ALT: Hold adagrasib therapy. When AST and ALT return to grade 1 or less or baseline, reduce the dose of adagrasib to the next lower dose level and resume therapy.
-AST or ALT increased more than 3 times the upper limit of normal (ULN) AND total bilirubin more than 2 times ULN in the absence of other causes: Permanently discontinue adagrasib therapy.
Patients with Renal Impairment Dosing
Baseline Renal Impairment
-Mild, Moderate, or Severe Renal Impairment (CrCl 15 to 89 mL/min): Dosage adjustments are not necessary.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with adagrasib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Abemaciclib: (Major) If coadministration with adagrasib is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If adagrasib is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of adagrasib. Abemaciclib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and adagrasib; significantly increased acalabrutinib exposure may occur. If short-term adagrasib use is necessary, interrupt acalabrutinib therapy. Acalabrutinib is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. In healthy subjects, the AUC of acalabrutinib was increased by 5.1-fold when acalabrutinib was coadministered with another strong inhibitor for 5 days.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with adagrasib may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of adagrasib could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If adagrasib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A; adagrasib is a dual moderate 2D6 and strong 3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with adagrasib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of adagrasib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If adagrasib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Adagrasib is a dual moderate CYP2D6 and strong CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A and CYP2D6 substrate, and coadministration with dual CYP3A and CYP2D6 inhibitors like adagrasib can significantly increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when added to a stable dose of hydrocodone. If adagrasib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. If adagrasib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with strong CYP3A inhibitors like adagrasib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If adagrasib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ado-Trastuzumab emtansine: (Major) Avoid coadministration of adagrasib with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until adagrasib has cleared from the circulation (approximately 3 half-lives of adagrasib) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A and to a lesser extent by CYP3A5; adagrasib is a strong CYP3A inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
Afatinib: (Moderate) If the concomitant use of adagrasib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of adagrasib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-gp substrate and adagrasib is a P-gp inhibitor. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC of afatinib was 119% when coadministered with the same P-gp inhibitor, and 111% when the inhibitor was administered 6 hours after afatinib.
Albuterol; Budesonide: (Moderate) Avoid coadministration of oral budesonide and adagrasib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; adagrasib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. If adagrasib is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A substrate, and coadministration with CYP3A inhibitors like adagrasib can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If adagrasib is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alfuzosin: (Contraindicated) Coadministration of alfuzosin and adagrasib is contraindicated due to increased alfuzosin exposure and the additive risk of QT/QTc prolongation and torsade de pointes (TdP). Alfuzosin is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. When coadministered with another strong CYP3A inhibitor, the AUC of alfuzosin was increased by 2.5-fold to 3.2-fold.
Almotriptan: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with adagrasib is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and adagrasib should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased almotriptan exposure by approximately 60%.
Alosetron: (Moderate) Concomitant use of alosetron with adagrasib may result in increased serum concentrations of alosetron and increase the risk for adverse reactions. Caution and close monitoring are advised if these drugs are used together. Alosetron is a substrate of hepatic isoenzyme CYP3A; adagrasib is a strong inhibitor of this enzyme. In a study of healthy female subjects, another strong CYP3A inhibitor increased mean alosetron AUC by 29%.
Alprazolam: (Contraindicated) Coadministration of alprazolam and adagrasib is contraindicated due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with adagrasib, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with other strong CYP3A inhibitors increased alprazolam exposure by 2.7- to 3.98-fold.
Amiodarone: (Major) Avoid concomitant use of amiodarone and adagrasib due to increased amiodarone exposure and an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Amiodarone is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation.
Amisulpride: (Major) Concomitant use of adagrasib and amisulpride increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Amitriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with adagrasib is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; adagrasib is a CYP2D6 inhibitor.
Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with adagrasib is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Atorvastatin: (Major) Coadministration of atorvastatin with adagrasib may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with adagrasib is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with adagrasib is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Celecoxib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with adagrasib is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with adagrasib is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with adagrasib is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with adagrasib is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Amobarbital: (Major) Avoid concurrent use of adagrasib and barbiturates due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Amoxapine: (Major) Lower doses of amoxapine may be required during concurrent use of adagrasib due to the potential for increased amoxapine exposure. If adagrasib is discontinued, an increased dose of amoxapine may be necessary. Amoxapine is a CYP2D6 substrate; adagrasib is a CYP2D6 inhibitor.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of clarithromycin with adagrasib due to the potential for increased exposure to adagrasib and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation) and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use before adagrasib steady state is achieved may increase adagrasib exposure. Adagrasib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state. (Moderate) Monitor for omeprazole-related adverse effects during coadministration with adagrasib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Anagrelide: (Major) Concomitant use of adagrasib and anagrelide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Apalutamide: (Major) Avoid concurrent use of adagrasib and apalutamide due to the risk of decreased adagrasib exposure which may reduce its efficacy. Additionally, the exposure of apalutamide may also be increased. Adagrasib is a CYP3A substrate and strong CYP3A inhibitor; apalutamide is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%. Concomitant use with a strong CYP3A inhibitor is predicted to increase the apalutamide AUC by 51%. The exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
Apomorphine: (Major) Concomitant use of adagrasib and apomorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Aprepitant, Fosaprepitant: (Major) Avoid coadministration of adagrasib and aprepitant/fosaprepitant due to substantially increased exposure of aprepitant. Fosaprepitant is rapidly converted to aprepitant; therefore, a similar interaction is likely. Aprepitant is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Administration of a strong CYP3A inhibitor increased the aprepitant AUC and mean terminal half-life by approximately 5-fold and 3-fold, respectively.
Aripiprazole: (Major) Concomitant use of aripiprazole and adagrasib increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and increases aripiprazole exposure and risk for side effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, an aripiprazole dosage reduction is required; management recommendations vary by aripiprazole dosage form. For aripiprazole oral dosage forms, administer a quarter of the usual dose. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 200 mg/month or from 300 mg to 160 mg/month. For extended-release aripiprazole injections given once every 2 months (Abilify Asimtufii), reduce the dosage from 960 mg to 720 mg; avoid use in patients known to be poor metabolizers of CYP2D6. Further dosage reductions may be required in patients who are also receiving a strong CYP2D6 inhibitor; see individual product prescribing information for details. Aripiprazole is CYP2D6 and CYP3A substrate, adagrasib is a moderate CYP2D6 and strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. (Major) Concomitant use of aripiprazole and adagrasib increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and increases aripiprazole exposure and risk for side effects. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Additionally, an aripiprazole dosage reduction is required; management recommendations vary by aripiprazole dosage form. For extended-release aripiprazole lauroxil injections (Aristada), reduce the dose to the next lowest strength; no dosage adjustment is required for patients tolerating 441 mg. For extended-release aripiprazole lauroxil injections (Aristada) in patients who are known to be poor metabolizers of CYP2D6, reduce the dose to 441 mg; no dosage adjustment is necessary for patients already tolerating 441 mg. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Further dosage reductions may be required in patients who are also receiving a strong CYP2D6 inhibitor; see individual product prescribing information for details. Aripiprazole is CYP2D6 and CYP3A substrate, adagrasib is a moderate CYP2D6 and strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation.
Arsenic Trioxide: (Major) Concomitant use of adagrasib and arsenic trioxide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Artemether; Lumefantrine: (Major) Avoid concomitant use of adagrasib and artemether due to the potential for increased artemether exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for artemether-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Artemether is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of artemether and dihydroartemisinin (an active metabolite of artemether) by 2.3- and 1.5-fold respectively. (Major) Avoid concomitant use of adagrasib and lumefantrine due to the potential for increased lumefantrine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for lumefantrine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Lumefantrine is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of lumefantrine by 1.6-fold.
Asciminib: (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with adagrasib is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Asenapine: (Major) Concomitant use of adagrasib and asenapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concurrent use of adagrasib and barbiturates due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with adagrasib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of adagrasib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If adagrasib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Adagrasib is a dual moderate CYP2D6 and strong CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Aspirin, ASA; Omeprazole: (Moderate) Monitor for omeprazole-related adverse effects during coadministration with adagrasib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. If adagrasib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with strong CYP3A inhibitors like adagrasib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If adagrasib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Moderate) Monitor for an increase in adagrasib-related adverse effects during concomitant use of atazanavir. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Atazanavir; Cobicistat: (Moderate) Monitor for an increase in adagrasib-related adverse effects during concomitant use of atazanavir. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state. (Moderate) Monitor for an increase in adverse effects from both drugs during concomitant use of adagrasib and cobicistat. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib and cobicistat are both CYP3A substrates and strong CYP3A inhibitors. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Atogepant: (Major) Avoid use of atogepant and adagrasib when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with adagrasib. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and adagrasib is a strong CYP3A inhibitor. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant overall exposure and a 2.15-fold increase in atogepant peak concentration.
Atomoxetine: (Major) Concomitant use of adagrasib and atomoxetine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Atorvastatin: (Major) Coadministration of atorvastatin with adagrasib may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Avacopan: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of adagrasib is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Avanafil: (Major) Do not use avanafil in patients receiving adagrasib due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration of other strong CYP3A inhibitors increased the avanafil AUC by 13-fold.
Avapritinib: (Major) Avoid coadministration of avapritinib with adagrasib due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor is predicted to increase the overall exposure of avapritinib by 600% at steady-state.
Axitinib: (Major) Avoid coadministration of axitinib with adagrasib due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after adagrasib is discontinued. Axitinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and adagrasib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Azithromycin: (Major) Concomitant use of adagrasib and azithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Barbiturates: (Major) Avoid concurrent use of adagrasib and barbiturates due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Bedaquiline: (Major) Avoid using bedaquiline and adagrasib together for more than 14 days as prolonged coadministration may increase the risk for bedaquiline toxicity and result in additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is required, monitor patients for bedaquiline-related adverse effects. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Bedaquiline is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Concurrent use of another strong CYP3A inhibitor increased bedaquiline exposure by 22%.
Benzhydrocodone; Acetaminophen: (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A and CYP2D6 substrate, and coadministration with dual CYP3A and CYP2D6 inhibitors like adagrasib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of benzhydrocodone. If adagrasib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to benzhydrocodone.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving adagrasib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving adagrasib. Concurrent use may increase betrixaban exposure resulting in an increased bleeding risk; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a P-gp substrate; adagrasib is a P-gp inhibitor. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2 to 3-fold.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with adagrasib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and adagrasib is a P-gp inhibitor.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Concomitant use of adagrasib and metronidazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Concomitant use of adagrasib and metronidazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Bortezomib: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of adagrasib is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased bortezomib exposure by 35%.
Bosentan: (Major) Avoid concomitant use of adagrasib and bosentan as the systemic exposure of bosentan may be increased resulting in an increase in treatment-related adverse reactions. Bosentan is a CYP2C9 and CYP3A substrate; adagrasib is a moderate CYP2C9 and strong CYP3A inhibitor.
Bosutinib: (Major) Avoid concomitant use of bosutinib and adagrasib; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A inhibitor.
Brentuximab vedotin: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with adagrasib is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased MMAE exposure by approximately 34%.
Brexpiprazole: (Major) Reduce the brexpiprazole dose to one quarter of the usual dose if coadministered with adagrasib. If adagrasib is discontinued, adjust the brexpiprazole dosage to its original level. Concomitant use may increase brexpiprazole exposure. Brexpiprazole is a CYP3A and CYP2D6 substrate and adagrasib is a strong CYP3A and moderate CYP2D6 inhibitor. Concomitant use of strong CYP3A inhibitors with or without a moderate CYP2D6 inhibitor increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
Brigatinib: (Major) Avoid coadministration of brigatinib with adagrasib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of adagrasib, resume the brigatinib dose that was tolerated prior to initiation of adagrasib. Brigatinib is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC of brigatinib by 101%.
Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with adagrasib ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A; adagrasib is a strong inhibitor of CYP3A.
Budesonide: (Moderate) Avoid coadministration of oral budesonide and adagrasib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; adagrasib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and adagrasib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; adagrasib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of oral budesonide and adagrasib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; adagrasib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with adagrasib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Bupivacaine; Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with adagrasib is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and adagrasib is a moderate CYP2C9 inhibitor.
Buprenorphine: (Major) Avoid concomitant use of adagrasib and buprenorphine due to the potential for increased buprenorphine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, consider a buprenorphine dosage reduction until stable drug effects are achieved. Monitor for respiratory depression and sedation at frequent intervals and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Buprenorphine is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Buprenorphine; Naloxone: (Major) Avoid concomitant use of adagrasib and buprenorphine due to the potential for increased buprenorphine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, consider a buprenorphine dosage reduction until stable drug effects are achieved. Monitor for respiratory depression and sedation at frequent intervals and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Buprenorphine is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Buspirone: (Moderate) A low dose of buspirone used cautiously is recommended when coadministered with adagrasib. If a patient has been titrated to a stable dosage of buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone. Administering adagrasib with buspirone may increase buspirone concentration and risk for adverse events. Buspirone is a sensitive substrate of CYP3A; adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the buspirone AUC by 19-fold with an increased incidence of buspirone-related adverse effects.
Butalbital; Acetaminophen: (Major) Avoid concurrent use of adagrasib and barbiturates due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concurrent use of adagrasib and barbiturates due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concurrent use of adagrasib and barbiturates due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%. (Moderate) Concomitant use of codeine with adagrasib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of adagrasib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If adagrasib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Adagrasib is a dual moderate CYP2D6 and strong CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concurrent use of adagrasib and barbiturates due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%. (Moderate) Concomitant use of codeine with adagrasib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of adagrasib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If adagrasib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Adagrasib is a dual moderate CYP2D6 and strong CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with adagrasib if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A and adagrasib is a strong CYP3A inhibitor. In a drug interaction study, coadministration with another strong CYP3A inhibitor increased cabazitaxel exposure by 25%.
Cabotegravir; Rilpivirine: (Major) Avoid concomitant use of adagrasib and rilpivirine due to the potential for increased rilpivirine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for rilpivirine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Rilpivirine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Both medications have been associated with QT interval prolongation, however, the degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Cabozantinib: (Major) Avoid concomitant use of cabozantinib and adagrasib due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with adagrasib 2 to 3 days after discontinuation of adagrasib. Cabozantinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
Capivasertib: (Major) Avoid coadministration of capivasertib with adagrasib due to increased capivasertib exposure which may increase the risk for capivasertib-related adverse effects. If coadministration is necessary, reduce the dose of capivasertib to 320 mg PO twice daily for 4 days followed by 3 days off; monitor for adverse reactions. Capivasertib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor is predicted to increase the overall exposure of capivasertib by up to 1.7-fold.
Capmatinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with adagrasib is necessary. Capmatinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased capmatinib exposure by 42%.
Carbamazepine: (Major) Avoid concurrent use of adagrasib and carbamazepine due to the risk of decreased adagrasib exposure which may reduce its efficacy. The exposure of carbamazepine may also be increased. Adagrasib is a CYP3A substrate and strong CYP3A inhibitor and carbamazepine is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Cariprazine: (Major) The dose of cariprazine should be reduced in patients also receiving adagrasib. When adagrasib is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When initiating cariprazine in a patient who is stable on adagrasib, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, and then increased to a maximum dose of 3 mg daily. When adagrasib is withdrawn, the cariprazine dosage may need to be increased. Cariprazine is metabolized by CYP3A to its major active metabolite; adagrasib is a strong CYP3A inhibitor. Concurrent use with another strong CYP3A inhibitor increased the exposure of cariprazine by about 4-fold; increased the AUC of DDCAR metabolite by about 1.5-fold; and decreased DCAR metabolite AUC by about one-third.
Carvedilol: (Moderate) Monitor for signs of bradycardia or heart block if coadministration of carvedilol with adagrasib is necessary. Carvedilol is a CYP2C9 substrate and adagrasib is a CYP2C9 inhibitor. Concomitant use may enhance the beta-blocking properties of carvedilol resulting in further slowing of the heart rate or cardiac conduction.
Celecoxib; Tramadol: (Moderate) Concurrent use of tramadol with adagrasib may produce unpredictable effects, including prolonged opioid-related adverse reactions, such as fatal respiratory depression, a withdrawal syndrome in those with physical dependence to opioid agonists, seizures, or serotonin syndrome. Consider dose adjustments of tramadol until stable drug effects are achieved. Monitor patients closely for respiratory depression and sedation at frequent intervals. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Tramadol is primarily metabolized by CYP2D6 to the active metabolite M1, and by CYP3A; adagrasib is a dual moderate CYP2D6 and strong CYP3A inhibitor. CYP3A inhibitors may increase tramadol-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Ceritinib: (Major) Avoid concomitant use of ceritinib with adagrasib. Concomitant use may increase the concentrations of both drugs and result in additive risk for QT/QTc prolongation. If concomitant use is necessary, avoid administration during adagrasib therapy initiation (approximately 8 days) and decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg. Monitor for side effects from both medications and consider taking steps to minimize the risk for QT/QTc interval prolongation and torsade de pointes (TdP), such as electrolyte monitoring and repletion and ECG monitoring. Both medications are CYP3A substrates and strong CYP3A inhibitors. Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted once steady state is reached.
Chloramphenicol: (Moderate) Monitor for an increase in adagrasib-related adverse effects during concomitant use of chloramphenicol. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Chlordiazepoxide: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with adagrasib is necessary; adjust the dose of chlordiazepoxide if necessary. Chlordiazepoxide is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor.
Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with adagrasib is necessary; adjust the dose of chlordiazepoxide if necessary. Chlordiazepoxide is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with adagrasib is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; adagrasib is a CYP2D6 inhibitor.
Chlordiazepoxide; Clidinium: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with adagrasib is necessary; adjust the dose of chlordiazepoxide if necessary. Chlordiazepoxide is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor.
Chloroquine: (Major) Concomitant use of adagrasib and chloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with adagrasib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of adagrasib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If adagrasib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Adagrasib is a dual moderate CYP2D6 and strong CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A and CYP2D6 substrate, and coadministration with dual CYP3A and CYP2D6 inhibitors like adagrasib can significantly increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when added to a stable dose of hydrocodone. If adagrasib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpromazine: (Major) Concomitant use of adagrasib and chlorpromazine increases the risk of QT/QTc prolongation, torsade de pointes (TdP), and other chlorpromazine-related adverse reactions. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. If concomitant use is necessary, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, and monitor for an increase in other chlorpromazine-related adverse reactions, including anticholinergic effects, orthostasis, and somnolence. Chlorpromazine is a CYP2D6 substrate and adagrasib is a moderate CYP2D6 inhibitor.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with adagrasib and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the cilostazol AUC by 117%.
Cinacalcet: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of adagrasib and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Ciprofloxacin: (Major) Concomitant use of adagrasib and ciprofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Cisapride: (Contraindicated) Concomitant use of cisapride and adagrasib is contraindicated; use increases cisapride exposure and the risk for adverse effects such as QT/QTc prolongation and torsade de pointes (TdP). Cisapride is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use of cisapride with CYP3A inhibitors is disallowed under the Propulsid Limited Access Program. Additionally, both medications may prolong QT/QTc interval and increase the risk for TdP.
Citalopram: (Major) Concomitant use of adagrasib and citalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clarithromycin: (Major) Avoid coadministration of clarithromycin with adagrasib due to the potential for increased exposure to adagrasib and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation) and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use before adagrasib steady state is achieved may increase adagrasib exposure. Adagrasib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Clindamycin: (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of adagrasib as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A substrate; adagrasib is a strong inhibitor of CYP3A.
Clofazimine: (Major) Concomitant use of adagrasib and clofazimine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Clomipramine: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with adagrasib is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; adagrasib is a CYP2D6 inhibitor.
Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with adagrasib; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Clorazepate: (Moderate) Monitor for an increase in sedation and respiratory depression if coadministration of clorazepate with adagrasib is necessary. Concurrent use may increase clorazepate exposure. Clorazepate is a prodrug whose active metabolite (N-desmethyldiazepam) is a CYP3A substrate. Adagrasib is a strong CYP3A inhibitor.
Clozapine: (Major) Avoid concomitant use of adagrasib and clozapine due to the potential for increased clozapine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for clozapine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Clozapine is a CYP3A and CYP2D6 substrate, adagrasib is a strong CYP3A and moderate CYP2D6 inhibitor, and both medications have been associated with QT interval prolongation.
Cobicistat: (Moderate) Monitor for an increase in adverse effects from both drugs during concomitant use of adagrasib and cobicistat. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib and cobicistat are both CYP3A substrates and strong CYP3A inhibitors. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Cobimetinib: (Major) Avoid coadministration of adagrasib with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. Coadministration with another strong CYP3A inhibitor increased cobimetinib exposure by 6.7-fold.
Codeine: (Moderate) Concomitant use of codeine with adagrasib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of adagrasib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If adagrasib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Adagrasib is a dual moderate CYP2D6 and strong CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with adagrasib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of adagrasib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If adagrasib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Adagrasib is a dual moderate CYP2D6 and strong CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with adagrasib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of adagrasib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If adagrasib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Adagrasib is a dual moderate CYP2D6 and strong CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of adagrasib and promethazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of codeine with adagrasib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of adagrasib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If adagrasib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Adagrasib is a dual moderate CYP2D6 and strong CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Promethazine: (Major) Concomitant use of adagrasib and promethazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Concomitant use of codeine with adagrasib may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of adagrasib could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If adagrasib is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Adagrasib is a dual moderate CYP2D6 and strong CYP3A inhibitor. CYP3A inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Colchicine: (Major) Avoid concomitant use of colchicine and adagrasib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and adagrasib is a dual strong CYP3A and P-gp inhibitor. Concomitant use with other dual strong CYP3A and P-gp inhibitors has been observed to increase colchicine overall exposure by 3- to 4-fold.
Conivaptan: (Contraindicated) Coadministration of conivaptan and adagrasib is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; adagrasib is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
Conjugated Estrogens; Medroxyprogesterone: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Copanlisib: (Major) Avoid the concomitant use of copanlisib and adagrasib if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor.
Crizotinib: (Major) Avoid concomitant use of crizotinib and adagrasib due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de points (TdP). If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Crizotinib is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with adagrasib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with adagrasib is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/minute. Avoid coadministration in patients with CrCl less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCl less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-gp substrate and adagrasib is a P-gp inhibitor.
Dabrafenib: (Major) Avoid coadministration of dabrafenib and adagrasib due to increased dabrafenib exposure. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity. Dabrafenib is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the dabrafenib AUC by 71%, hydroxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%.
Dapagliflozin; Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with adagrasib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the saxagliptin AUC up to 3.7-fold.
Daridorexant: (Major) Avoid concomitant use of daridorexant and adagrasib. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Darifenacin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with adagrasib due to increased darifenacin exposure. Darifenacin is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor.
Darunavir: (Moderate) Monitor for an increase in adverse effects from both drugs during concomitant use of adagrasib and darunavir. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib and darunavir are both CYP3A substrates and strong CYP3A inhibitors. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Darunavir; Cobicistat: (Moderate) Monitor for an increase in adverse effects from both drugs during concomitant use of adagrasib and cobicistat. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib and cobicistat are both CYP3A substrates and strong CYP3A inhibitors. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state. (Moderate) Monitor for an increase in adverse effects from both drugs during concomitant use of adagrasib and darunavir. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib and darunavir are both CYP3A substrates and strong CYP3A inhibitors. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with adagrasib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and adagrasib is a P-gp inhibitor. (Moderate) Monitor for an increase in adverse effects from both drugs during concomitant use of adagrasib and cobicistat. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib and cobicistat are both CYP3A substrates and strong CYP3A inhibitors. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state. (Moderate) Monitor for an increase in adverse effects from both drugs during concomitant use of adagrasib and darunavir. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib and darunavir are both CYP3A substrates and strong CYP3A inhibitors. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Dasatinib: (Major) Avoid coadministration of dasatinib and adagrasib due to the potential for increased dasatinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Stop dasatinib during use of adagrasib in patients receiving dasatinib 60 mg or 40 mg PO daily. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. If dasatinib is not tolerated after dose reduction, either discontinue adagrasib or stop dasatinib until adagrasib is discontinued. Allow a washout of approximately 1 week after adagrasib is stopped before increasing the dasatinib dose or reinitiating dasatinib. Dasatinib is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications may prolong the QT/QTc interval. Coadministration with another strong CYP3A inhibitor increased the AUC of dasatinib by 5-fold.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with adagrasib. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A substrate; adagrasib is a strong inhibitor of CYP3A. Administration of deflazacort with another strong CYP3A inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
Degarelix: (Major) Concomitant use of adagrasib and androgen deprivation therapy (i.e., degarelix) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Delavirdine: (Moderate) Monitor for an increase in adagrasib-related adverse effects during concomitant use of delavirdine. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Desflurane: (Major) Concomitant use of adagrasib and halogenated anesthetics increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Desipramine: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with adagrasib is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; adagrasib is a CYP2D6 inhibitor.
Desogestrel; Ethinyl Estradiol: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Dexamethasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of adagrasib with dexamethasone is necessary, due to increased dexamethasone exposure; Cushing's syndrome and adrenal suppression could potentially occur with long-term use. Consider the use of corticosteroids such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A inhibitors, especially for long-term use. Dexamethasone is primarily metabolized by CYP3A and adagrasib is a strong CYP3A inhibitor. Another strong CYP3A inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Dexlansoprazole: (Moderate) The plasma concentrations of dexlansoprazole may be elevated when administered concurrently with adagrasib. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Dexlansoprazole is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor.
Dexmedetomidine: (Major) Concomitant use of dexmedetomidine and adagrasib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dextromethorphan; Quinidine: (Major) Avoid concomitant use of adagrasib and quinidine due to the potential for increased quinidine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for quinidine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Quinidine is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with adagrasib is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and adagrasib is a CYP3A inhibitor.
Dienogest; Estradiol valerate: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Digoxin: (Moderate) Increase monitoring of serum digoxin concentrations and watch for potential signs and symptoms of clinical toxicity when starting, adjusting, or discontinuing adagrasib. Concurrent use may increase digoxin exposure. Digoxin is a P-gp substrate with a narrow therapeutic index and adagrasib is a P-gp inhibitor. Concomitant use of adagrasib 600 mg twice daily is predicted to increase digoxin overall exposure by 1.5-fold.
Dihydroergotamine: (Contraindicated) Concomitant use of ergotamine with adagrasib is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Diltiazem: (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with adagrasib is necessary. Concurrent use may result in elevated diltiazem concentrations. Diltiazem is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Disopyramide: (Major) Avoid concomitant use of adagrasib and disopyramide due to the potential for increased disopyramide exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for disopyramide-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Disopyramide is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Docetaxel: (Major) Avoid coadministration of docetaxel with adagrasib if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased docetaxel exposure by 2.2-fold.
Dofetilide: (Major) Avoid concomitant use of adagrasib and dofetilide due to the potential for increased dofetilide exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for dofetilide-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Dofetilide is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Dolasetron: (Major) Concomitant use of adagrasib and dolasetron increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with adagrasib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with adagrasib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Dolutegravir; Rilpivirine: (Major) Avoid concomitant use of adagrasib and rilpivirine due to the potential for increased rilpivirine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for rilpivirine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Rilpivirine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Both medications have been associated with QT interval prolongation, however, the degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with adagrasib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Donepezil: (Major) Avoid concomitant use of adagrasib and donepezil due to the potential for increased donepezil exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for donepezil-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Donepezil is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Donepezil; Memantine: (Major) Avoid concomitant use of adagrasib and donepezil due to the potential for increased donepezil exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for donepezil-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Donepezil is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Doravirine: (Minor) Coadministration of doravirine and adagrasib may result in increased doravirine plasma concentrations. Doravirine is a CYP3A substrate; adagrasib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with adagrasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and adagrasib is a P-gp inhibitor. (Minor) Coadministration of doravirine and adagrasib may result in increased doravirine plasma concentrations. Doravirine is a CYP3A substrate; adagrasib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doxazosin: (Moderate) Monitor blood pressure and for symptoms of hypotension if coadministration of doxazosin and adagrasib is necessary. Concurrent use may result in increased doxazosin exposure. Doxazosin is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Doxepin: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with adagrasib is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; adagrasib is a CYP2D6 inhibitor.
Doxorubicin Liposomal: (Major) Avoid coadministration of doxorubicin with adagrasib due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a CYP3A, CYP2D6, and P-gp substrate; adagrasib is a strong CYP3A, moderate CYP2D6, and P-gp inhibitor. Concurrent use of CYP3A, CYP2D6, or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of doxorubicin with adagrasib due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a CYP3A, CYP2D6, and P-gp substrate; adagrasib is a strong CYP3A, moderate CYP2D6, and P-gp inhibitor. Concurrent use of CYP3A, CYP2D6, or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Moderate) Monitor for increased toxicity (e.g., feeling high, dizziness, confusion, somnolence) of dronabinol if coadministered with adagrasib. Coadministration may increase the exposure of dronabinol. Dronabinol is a CYP3A and CYP2C9 substrate; adagrasib is a strong CYP3A and moderate CYP2C9 inhibitor.
Dronedarone: (Contraindicated) Coadministration of dronedarone with adagrasib is contraindicated due to the potential for increased dronedarone exposure and additive risk for QT prolongation. Dronedarone is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Droperidol: (Major) Concomitant use of adagrasib and droperidol increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Drospirenone: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Drospirenone; Estetrol: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Drospirenone; Estradiol: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Drospirenone; Ethinyl Estradiol: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Dutasteride: (Moderate) Monitor for dutasteride-related adverse reactions if coadministration with adagrasib is necessary. Dutasteride is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Although the effect of strong CYP3A inhibitors on dutasteride has not been studied, dutasteride exposure may increase.
Dutasteride; Tamsulosin: (Major) Concurrent use of tamsulosin and adagrasib is not recommended due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A and CYP2D6 substrate and adagrasib is a strong CYP3A and moderate CYP2D6 inhibitor. Concomitant treatment with another strong CYP3A inhibitor increased the AUC of tamsulosin by 2.8-fold. (Moderate) Monitor for dutasteride-related adverse reactions if coadministration with adagrasib is necessary. Dutasteride is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Although the effect of strong CYP3A inhibitors on dutasteride has not been studied, dutasteride exposure may increase.
Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity when coadministered with adagrasib. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as adagrasib.
Edoxaban: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of adagrasib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and adagrasib is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with adagrasib. Based on clinical experience in patients with non-valvular atrial fibrillation, no dose reduction is recommended for concomitant use of adagrasib. Increased concentrations of edoxaban may occur during concomitant use of adagrasib; monitor for increased adverse effects of edoxaban.
Efavirenz: (Major) Concomitant use of adagrasib and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Concomitant use of adagrasib and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Coadministration of tenofovir disoproxil fumarate with adagrasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and adagrasib is a P-gp inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Concomitant use of adagrasib and efavirenz increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Coadministration of tenofovir disoproxil fumarate with adagrasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and adagrasib is a P-gp inhibitor.
Elacestrant: (Major) Avoid concomitant use of elacestrant and adagrasib due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased elacestrant overall exposure by 5.3-fold.
Elagolix: (Major) Concomitant use of elagolix 200 mg twice daily and adagrasib for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and adagrasib to 6 months. Coadministration may increase elagolix exposure. Elagolix is a CYP3A substrate; adagrasib is a strong inhibitor of CYP3A. Coadministration of elagolix with another strong CYP3A inhibitor increased the AUC of elagolix by 120%.
Elagolix; Estradiol; Norethindrone acetate: (Major) Concomitant use of elagolix 200 mg twice daily and adagrasib for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and adagrasib to 6 months. Coadministration may increase elagolix exposure. Elagolix is a CYP3A substrate; adagrasib is a strong inhibitor of CYP3A. Coadministration of elagolix with another strong CYP3A inhibitor increased the AUC of elagolix by 120%. (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Elbasvir; Grazoprevir: (Moderate) Monitor for an increase in elbasvir-related adverse reactions if coadministration with adagrasib is necessary. Elbasvir is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased elbasvir exposure by almost 2-fold. (Moderate) Monitor for an increase in grazoprevir-related adverse reactions if coadministration with adagrasib is necessary. Grazoprevir is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased grazoprevir exposure by 3-fold.
Eletriptan: (Contraindicated) Eletriptan is contraindicated with recent use (i.e., within 72 hours) of adagrasib due to the potential for increased eletriptan exposure. Eletriptan is a sensitive substrate of CYP3A; adagrasib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the AUC of eletriptan by 6-fold.
Elexacaftor; tezacaftor; ivacaftor: (Major) If adagrasib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to twice a week in the morning, approximately 3 to 4 days apart (i.e., Day 1 and Day 4) when coadministered with adagrasib; omit the evening dose of ivacaftor. Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; adagrasib is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with adagrasib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, give one tezacaftor/ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Eliglustat: (Contraindicated) Coadministration of adagrasib and eliglustat is contraindicated. Concurrent use may result in unexpectedly high plasma concentrations of eliglustat, further increasing the risk of serious adverse events (e.g., cardiac arrhythmias). Concomitant use also results in additive risk for QT/QTc interval prolongation and torsade de pointes. Eliglustat is a CYP3A and CYP2D6 substrate and adagrasib is a strong CYP3A and moderate CYP2D6 inhibitor. Both medications have been associated with QT interval prolongation.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with adagrasib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and adagrasib is a P-gp inhibitor. (Moderate) Monitor for an increase in adverse effects from both drugs during concomitant use of adagrasib and cobicistat. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib and cobicistat are both CYP3A substrates and strong CYP3A inhibitors. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with adagrasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and adagrasib is a P-gp inhibitor. (Moderate) Monitor for an increase in adverse effects from both drugs during concomitant use of adagrasib and cobicistat. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib and cobicistat are both CYP3A substrates and strong CYP3A inhibitors. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Avoid concomitant use of adagrasib and rilpivirine due to the potential for increased rilpivirine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for rilpivirine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Rilpivirine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Both medications have been associated with QT interval prolongation, however, the degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. (Moderate) Coadministration of tenofovir alafenamide with adagrasib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and adagrasib is a P-gp inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of adagrasib and rilpivirine due to the potential for increased rilpivirine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for rilpivirine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Rilpivirine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Both medications have been associated with QT interval prolongation, however, the degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. (Moderate) Coadministration of tenofovir disoproxil fumarate with adagrasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and adagrasib is a P-gp inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with adagrasib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and adagrasib is a P-gp inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with adagrasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and adagrasib is a P-gp inhibitor.
Encorafenib: (Major) Avoid coadministration of encorafenib and adagrasib due to the risk of decreased adagrasib exposure, increased encorafenib exposure, and increased risk of QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Adagrasib is a CYP3A substrate and strong CYP3A inhibitor, encorafenib is a CYP3A substrate and strong CYP3A inducer, and both medications may prolong the QT interval. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Entrectinib: (Major) Avoid concomitant use of entrectinib with adagrasib due to the risk for increased entrectinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Entrectinib is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT/QTc prolongation. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Enzalutamide: (Major) Avoid concurrent use of adagrasib and enzalutamide due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Eplerenone: (Contraindicated) Eplerenone is contraindicated for use with adagrasib due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Adagrasib is a strong CYP3A inhibitor; eplerenone is a sensitive CYP3A substrate. Another strong CYP3A inhibitor increased serum eplerenone concentrations by roughly 5-fold.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and adagrasib due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If adagrasib is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP3A and CYP2C9 substrate and adagrasib is a strong CYP3A and moderate CYP2C9 inhibitor. The mean ratio for the AUC of erdafitinib was 134% when coadministered with another strong CYP3A inhibitor.
Ergotamine: (Contraindicated) Concomitant use of ergotamine with adagrasib is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Ergotamine; Caffeine: (Contraindicated) Concomitant use of ergotamine with adagrasib is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Eribulin: (Major) Concomitant use of adagrasib and eribulin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Erlotinib: (Major) Avoid coadministration of erlotinib with adagrasib if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased erlotinib exposure by 67%.
Erythromycin: (Major) Concomitant use of adagrasib and erythromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Escitalopram: (Major) Concomitant use of adagrasib and escitalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Esomeprazole: (Moderate) Monitor for esomeprazole-related adverse effects during coadministration with adagrasib. Concurrent use may increase esomeprazole exposure. Esomeprazole is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Estazolam: (Moderate) Monitor for estazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with adagrasib is necessary. Adagrasib is a strong CYP3A inhibitor and estazolam is primarily metabolized by CYP3A. In vivo drug-drug interaction studies were not conducted between estazolam and inhibitors of CYP3A.
Estradiol; Levonorgestrel: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Estradiol; Norethindrone: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Estradiol; Norgestimate: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Estradiol; Progesterone: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Eszopiclone: (Major) The total dose of eszopiclone should not exceed 2 mg when administered with adagrasib. Coadministration may increase eszopiclone exposure resulting in increased risk of next-day psychomotor or memory impairment and decreased ability to perform tasks requiring full mental alertness such as driving. CYP3A is a primary metabolic pathway for eszopiclone; adagrasib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased eszopiclone exposure by 2.2-fold.
Ethinyl Estradiol; Norelgestromin: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Ethinyl Estradiol; Norgestrel: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Ethosuximide: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with adagrasib is necessary. Ethosuximide is a CYP3A substrate with a narrow therapeutic index and adagrasib is a strong CYP3A inhibitor.
Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Etonogestrel: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Etonogestrel; Ethinyl Estradiol: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Etrasimod: (Major) Avoid concomitant use of etrasimod and adagrasib due to the risk for increased etrasimod exposure which may increase the risk for adverse effects. Concomitant use may also increase the risk for QT/QTc prolongation and torsade de pointes (TdP). Etrasimod is a CYP2C9 and CYP3A substrate and adagrasib is a moderate CYP2C9 and strong CYP3A inhibitor. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Etravirine: (Moderate) Monitor for an increase in etravirine-related adverse reactions if concomitant use of adagrasib is necessary. Etravirine is a CYP3A and CYP2C9 substrate and adagrasib is a strong CYP3A and moderate CYP2C9 inhibitor. Concomitant use of another strong CYP3A inhibitor increased etravirine exposure by 1.4-fold.
Everolimus: (Major) Avoid coadministration of everolimus with adagrasib due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. Coadministration with a strong CYP3A and P-gp inhibitor increased the overall exposure of everolimus by 15-fold.
Ezetimibe; Simvastatin: (Contraindicated) Concurrent use of simvastatin and adagrasib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Concomitant use my increase simvastatin exposure. Simvastatin is a sensitive CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Fedratinib: (Major) Avoid coadministration of fedratinib with adagrasib as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If adagrasib is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased fedratinib exposure by 3-fold.
Felodipine: (Moderate) Concurrent use of felodipine and adagrasib should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concurrent use of another strong CYP3A inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. If adagrasib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like adagrasib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If adagrasib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fesoterodine: (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with adagrasib. Avoid use of fesoterodine and adagrasib in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor led to approximately a doubling of the overall exposure of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine.
Fexinidazole: (Major) Avoid concomitant use of fexinidazole and adagrasib; concomitant use may reduce fexinidazole efficacy and increase the risk for QT/QTc interval prolongation and torsade de pointes (TdP). If concomitant use is necessary, monitor for decreased fexinidazole efficacy and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use may limit conversion of fexinidazole to its active metabolites. Fexinidazole is converted to its active metabolites via CYP3A and adagrasib is a strong CYP3A inhibitor.
Finasteride; Tadalafil: (Major) Avoid coadministration of tadalafil and adagrasib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of adagrasib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A. Potent inhibitors of CYP3A, such as adagrasib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Finerenone: (Contraindicated) Concomitant use of finerenone and adagrasib is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%.
Fingolimod: (Major) Concomitant use of adagrasib and fingolimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Flecainide: (Major) Avoid concomitant use of adagrasib and flecainide due to the potential for increased flecainide exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for flecainide-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Flecainide is a CYP2D6 substrate, adagrasib is a moderate CYP2D6 inhibitor, and both medications have been associated with QT interval prolongation.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and strong CYP3A inhibitors such as adagrasib is contraindicated due to increased flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following the use of adagrasib, start flibanserin at least 2 weeks after the last dose of adagrasib. If initiating adagrasib following flibanserin use, begin therapy at least 2 days after the last dose of flibanserin. In cases where the benefit of initiating adagrasib therapy within 2 days of stopping flibanserin clearly outweighs the risk of flibanserin-related hypotension and syncope, monitor the patient for signs of hypotension and syncope.
Fluconazole: (Contraindicated) Avoid concomitant use of adagrasib and fluconazole due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Coadministration of fluconazole with medications metabolized via CYP3A that are known to prolong the QT interval is contraindicated per the manufacturer of fluconazole. If concomitant use is necessary, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Adagrasib is a CYP3A substrate, fluconazole is a moderate CYP3A inhibitor, and both medications have been associated with QT interval prolongation. No clinically significant differences in adagrasib pharmacokinetics adagrasib are predicted with moderate CYP3A inhibitors.
Fluoxetine: (Major) Avoid concomitant use of adagrasib and fluoxetine due to the potential for increased fluoxetine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for fluoxetine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Fluoxetine is a CYP2D6 substrate, adagrasib is a moderate CYP2D6 inhibitor, and both medications have been associated with QT interval prolongation.
Fluphenazine: (Minor) QT/QTc prolongation can occur with concomitant use of adagrasib and fluphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Flurazepam: (Moderate) Monitor for an increase in flurazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with adagrasib is necessary. Concurrent use may increase flurazepam exposure. Flurazepam is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and adagrasib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Salmeterol: (Major) Avoid concomitant use of salmeterol with adagrasib. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Coadministration of inhaled fluticasone propionate and adagrasib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and adagrasib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Monitor for an increase in vilanterol-related adverse effects if coadministered with adagrasib. Coadministration may increase vilanterol exposure. Vilanterol is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor significantly increased systemic exposure to vilanterol.
Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and adagrasib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Monitor for an increase in vilanterol-related adverse effects if coadministered with adagrasib. Coadministration may increase vilanterol exposure. Vilanterol is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor significantly increased systemic exposure to vilanterol.
Fluvoxamine: (Major) Concomitant use of adagrasib and fluvoxamine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Food: (Major) Advise patients to avoid cannabis use during adagrasib treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A and CYP2C9 substrates and adagrasib is a strong CYP3A and moderate CYP2C9 inhibitor. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inhibitor increased THC, 11-OH-THC, and CBD peak exposure by 1.3-, 3-, and 1.9-fold respectively.
Formoterol; Mometasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of mometasone with adagrasib is necessary, due to increased mometasone exposure; Cushing's syndrome and adrenal suppression could potentially occur with long-term use. Mometasone is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Fosamprenavir: (Moderate) Monitor for increased fosamprenavir toxicity if coadministered with adagrasib. Concurrent use may increase the plasma concentrations of fosamprenavir. Fosamprenavir is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Foscarnet: (Major) Concomitant use of adagrasib and foscarnet increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Fosphenytoin: (Major) Avoid concurrent use of adagrasib and fosphenytoin due to the risk of decreased adagrasib exposure which may reduce its efficacy. The exposure of fosphenytoin may also be increased. Adagrasib is a CYP3A substrate and moderate CYP2C9 inhibitor and fosphenytoin is a CYP2C9 substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Fostamatinib: (Moderate) Monitor for an increase in treatment-related adverse reactions if coadministration of adagrasib with fostamatinib is necessary. Fostamatinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased exposure to R406 (the major active metabolite of fostamatinib) by 102%.
Fostemsavir: (Major) Concomitant use of adagrasib and fostemsavir increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with fostemsavir is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 4 times the recommended daily dose.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with adagrasib is necessary; the risk is increased in CYP2D6 poor metabolizers. Gefitinib is a CYP3A and CYP2D6 substrate and adagrasib is a strong CYP3A and moderate CYP2D6 inhibitor. Coadministration with another strong CYP3A inhibitor increased gefitinib exposure by 80%. The mean exposure of gefitinib was 2-fold higher in healthy CYP2D6 poor metabolizers compared to extensive metabolizers.
Gemifloxacin: (Major) Concomitant use of adagrasib and gemifloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Gemtuzumab Ozogamicin: (Major) Concomitant use of adagrasib and gemtuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Gilteritinib: (Major) Avoid concomitant use of adagrasib and gilteritinib. Concurrent use may increase gilteritinib exposure and increase the risk for QT/QTc interval prolongation and torsade de pointes (TdP). If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Gilteritinib is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications may prolong the QT interval. Coadministration of a strong CYP3A inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
Glasdegib: (Major) Avoid concomitant use of adagrasib and glasdegib. Concurrent use may increase glasdegib exposure and increase the risk for QT/QTc interval prolongation and torsade de pointes (TdP). If coadministration is necessary, monitor for increased adverse events and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Glasdegib is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications increase the risk for QT interval prolongation. Coadministration of a strong CYP3A inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and adagrasib as increased plasma concentrations of glecaprevir may occur resulting in increased risk of glecaprevir-related adverse events. Glecaprevir is a substrate of P-gp and adagrasib is a P-gp inhibitor. (Moderate) Monitor for an increase in pibrentasvir-related adverse effects if concomitant use of adagrasib is necessary. Concomitant use may increase pibrentasvir exposure. Pibrentasvir is a substrate of P-gp and adagrasib is a P-gp inhibitor.
Glimepiride: (Moderate) Monitor for an increase in glimepiride-related adverse reactions, such as hypoglycemia, if coadministration with adagrasib is necessary. Concomitant use may increase glimepiride exposure. Glimepiride is a CYP2C9 substrate; adagrasib is a moderate CYP2C9 inhibitor.
Glipizide: (Moderate) Monitor for an increase in glipizide-related adverse reactions, such as hypoglycemia, if coadministration with adagrasib is necessary. Concomitant use may increase glipizide exposure. Glipizide is a CYP2C9 substrate; adagrasib is a moderate CYP2C9 inhibitor.
Glipizide; Metformin: (Moderate) Monitor for an increase in glipizide-related adverse reactions, such as hypoglycemia, if coadministration with adagrasib is necessary. Concomitant use may increase glipizide exposure. Glipizide is a CYP2C9 substrate; adagrasib is a moderate CYP2C9 inhibitor.
Glyburide: (Moderate) Monitor for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with adagrasib is necessary. Concomitant use may increase glyburide exposure. Glyburide is a CYP2C9 substrate; adagrasib is a moderate CYP2C9 inhibitor.
Glyburide; Metformin: (Moderate) Monitor for an increase in glyburide-related adverse reactions, such as hypoglycemia, if coadministration with adagrasib is necessary. Concomitant use may increase glyburide exposure. Glyburide is a CYP2C9 substrate; adagrasib is a moderate CYP2C9 inhibitor.
Goserelin: (Major) Concomitant use of adagrasib and androgen deprivation therapy (i.e., goserelin) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Granisetron: (Major) Avoid concomitant use of adagrasib and granisetron due to the potential for increased granisetron exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for granisetron-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Granisetron is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during adagrasib treatment due to the risk of increased adagrasib exposure and adverse reactions. Adagrasib is a CYP3A substrate and grapefruit juice is a strong CYP3A inhibitor.
Guanfacine: (Major) If coadministration of adagrasib with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for adverse effects including hypotension, drowsiness, lethargy, and bradycardia. If adagrasib is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor; adagrasib may significantly increase guanfacine plasma concentrations.
Halogenated Anesthetics: (Major) Concomitant use of adagrasib and halogenated anesthetics increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Haloperidol: (Major) Avoid concomitant use of adagrasib and haloperidol due to the potential for increased haloperidol exposure, haloperidol-related side effects, and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for haloperidol-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Haloperidol is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. The intravenous route may carry a higher risk for haloperidol-induced QT/QTc prolongation than other routes of administration.
Histrelin: (Major) Concomitant use of adagrasib and androgen deprivation therapy (i.e., histrelin) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A and CYP2D6 substrate, and coadministration with dual CYP3A and CYP2D6 inhibitors like adagrasib can significantly increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when added to a stable dose of hydrocodone. If adagrasib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A and CYP2D6 substrate, and coadministration with dual CYP3A and CYP2D6 inhibitors like adagrasib can significantly increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when added to a stable dose of hydrocodone. If adagrasib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A and CYP2D6 substrate, and coadministration with dual CYP3A and CYP2D6 inhibitors like adagrasib can significantly increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when added to a stable dose of hydrocodone. If adagrasib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydroxychloroquine: (Major) Concomitant use of adagrasib and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Hydroxyzine: (Major) Concomitant use of adagrasib and hydroxyzine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with adagrasib. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of ibrexafungerp by 5.8-fold.
Ibrutinib: (Major) Avoid concomitant use of ibrutinib and adagrasib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). If short-term use of adagrasib is necessary (e.g., 7 days or less), interrupt ibrutinib treatment. Resume ibrutinib at the previous dose when adagrasib is discontinued. Ibrutinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with other strong CYP3A inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. If adagrasib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with strong CYP3A inhibitors like adagrasib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If adagrasib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ibutilide: (Major) Concomitant use of adagrasib and ibutilide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Idelalisib: (Major) Avoid concomitant use of idelalisib with adagrasib and consider alternative therapy. Concomitant use may increase idelalisib exposure and the risk for idelalisib-related adverse reactions. Additionally, concomitant use during adagrasib therapy initiation before steady state is reached (approximately 8 days) may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. If concomitant use is necessary, monitor patients frequently for signs and symptoms of adverse reactions from either drug (e.g., QT prolongation, hepatotoxicity, diarrhea, neutropenia, and infection). Both idelalisib and adagrasib are CYP3A substrates and strong CYP3A inhibitors. Coadministration with another strong CYP3A inhibitor increased idelalisib exposure by 1.8-fold. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with adagrasib is necessary. Ifosfamide is metabolized by CYP3A to its active alkylating metabolites. Adagrasib is a strong CYP3A inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) Avoid coadministration of iloperidone and adagrasib due to the potential for increased iloperidone exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, reduce the iloperidone dose by one-half and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. If adagrasib is discontinued, increase the iloperidone dose to the previous level. Iloperidone is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration of another strong CYP3A inhibitor increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively.
Imatinib: (Moderate) Monitor for an increase in imatinib-related adverse reactions if coadministration with adagrasib is necessary. Imatinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased imatinib exposure by 40%.
Imipramine: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with adagrasib is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; adagrasib is a CYP2D6 inhibitor.
Indinavir: (Moderate) Monitor for an increase in adverse effects from both drugs during concomitant use of adagrasib and indinavir. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Although specific recommendations are unavailable for use with adagrasib, a reduced indinavir dose of 600 mg PO every 8 hours is recommended when coadministered with other strong CYP3A inhibitors. Adagrasib and indinavir are both CYP3A substrates and strong CYP3A inhibitors. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Infigratinib: (Major) Avoid concomitant use of infigratinib and adagrasib. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of infigratinib by 622%.
Inotuzumab Ozogamicin: (Major) Concomitant use of adagrasib and inotuzumab increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Irinotecan Liposomal: (Major) Avoid administration of adagrasib during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A substrates. Adagrasib is a strong CYP3A inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Irinotecan: (Major) Avoid administration of adagrasib during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A substrates. Adagrasib is a strong CYP3A inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Isavuconazonium: (Contraindicated) Coadministration of isavuconazonium with adagrasib is contraindicated due to the risk of increased isavuconazole exposure. Isavuconazole is a sensitive substrate of CYP3A and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased isavuconazole exposure by 422%.
Isoflurane: (Major) Concomitant use of adagrasib and halogenated anesthetics increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concurrent use of adagrasib and rifampin due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use with rifampin reduced adagrasib exposure by more than 66%.
Isoniazid, INH; Rifampin: (Major) Avoid concurrent use of adagrasib and rifampin due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use with rifampin reduced adagrasib exposure by more than 66%.
Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with adagrasib is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with adagrasib as istradefylline exposure and adverse effects may increase. Istradefylline is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong CYP3A inhibitor in a drug interaction study.
Itraconazole: (Contraindicated) Avoid concomitant use of adagrasib and itraconazole. Concomitant use may increase concentrations of both medications and result in additive risk for QT/QTc prolongation and torsade de pointes (TdP). The use of itraconazole with a CYP3A substrate that causes QT prolongation, such as adagrasib, is contraindicated per the manufacturer of itraconazole. If use is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation), monitor for itraconazole-related adverse effects, and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use before adagrasib steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and strong CYP3A inhibitor, itraconazole is a CYP3A substrate and strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with itraconazole increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Ivabradine: (Contraindicated) Coadministration of adagrasib with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivabradine exposure by 7.7-fold.
Ivacaftor: (Major) If adagrasib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with adagrasib due to the potential for increased ivosidenib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, reduce the dose of ivosidenib to 250 mg PO once daily and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. If adagrasib is discontinued, wait at least 5 half-lives of adagrasib before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Ixabepilone: (Major) Avoid concurrent use of ixabepilone and adagrasib due to increased ixabepilone exposure, which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of ixabepilone to 20 mg/m2. Ixabepilone is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ixabepilone exposure by 79%.
Ketoconazole: (Contraindicated) Avoid concomitant use of adagrasib and ketoconazole. Concomitant use may increase concentrations of both medications and result in additive risk for QT/QTc prolongation and torsade de pointes (TdP). Per the manufacturer of levoketoconazole, use with other agents that cause QT prolongation is contraindicated. If use is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation), consider a ketoconazole dosage reduction, and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use before adagrasib steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Both medications are CYP3A substrates and strong CYP3A inhibitors. Both medications have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with adagrasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and adagrasib is a P-gp inhibitor.
Lansoprazole: (Moderate) Monitor for lansoprazole-related adverse effects during coadministration with adagrasib. Concurrent use may increase lansoprazole exposure. Lansoprazole is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of clarithromycin with adagrasib due to the potential for increased exposure to adagrasib and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation) and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use before adagrasib steady state is achieved may increase adagrasib exposure. Adagrasib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state. (Moderate) Monitor for lansoprazole-related adverse effects during coadministration with adagrasib. Concurrent use may increase lansoprazole exposure. Lansoprazole is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Lapatinib: (Major) Avoid coadministration of lapatinib with adagrasib due to increased plasma concentrations of lapatinib and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, decrease the dose of lapatinib to 500 mg PO once daily and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. If adagrasib is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A and P-gp substrate, adagrasib is a strong CYP3A and P-gp inhibitor, and both medications have been associated with QT interval prolongation. Concomitant use with another strong CYP3A inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold.
Larotrectinib: (Major) Avoid coadministration of adagrasib with larotrectinib due to the risk of increased larotrectinib exposure which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of larotrectinib by 50%. After adagrasib has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose taken prior to initiating adagrasib. Larotrectinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the larotrectinib AUC by 4.3-fold.
Lefamulin: (Major) Avoid coadministration of adagrasib with lefamulin. Concomitant use may produce additive risk for QT/QTc prolongation and torsade de pointes (TdP) and may increase oral lefamulin exposure. Concentrations of intravenous lefamulin may be less affected. Lefamulin is a CYP3A and P-gp substrate, adagrasib is a strong CYP3A and P-gp inhibitor, and both medications have been associated with QT interval prolongation. Coadministration of a strong CYP3A inhibitor increased the exposure of oral lefamulin by 165%; the exposure to intravenous lefamulin was increased by 31%.
Lemborexant: (Major) Avoid coadministration of lemborexant and adagrasib as concomitant use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the lemborexant overall exposure by up to 4.5-fold.
Leniolisib: (Major) Avoid concomitant use of leniolisib and adagrasib due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Leniolisib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased leniolisib overall exposure by 2-fold.
Lenvatinib: (Major) Concomitant use of adagrasib and lenvatinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Leuprolide: (Major) Concomitant use of adagrasib and androgen deprivation therapy (i.e., leuprolide) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Leuprolide; Norethindrone: (Major) Concomitant use of adagrasib and androgen deprivation therapy (i.e., leuprolide) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with adagrasib is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Levofloxacin: (Major) Concomitant use of adagrasib and levofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Levoketoconazole: (Contraindicated) Avoid concomitant use of adagrasib and ketoconazole. Concomitant use may increase concentrations of both medications and result in additive risk for QT/QTc prolongation and torsade de pointes (TdP). Per the manufacturer of levoketoconazole, use with other agents that cause QT prolongation is contraindicated. If use is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation), consider a ketoconazole dosage reduction, and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use before adagrasib steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Both medications are CYP3A substrates and strong CYP3A inhibitors. Both medications have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Levomilnacipran: (Major) Do not exceed a levomilnacipran dose of 80 mg once daily if coadministration with adagrasib is necessary. Concomitant use may increase levomilnacipran exposure. Levomilnacipran is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased levomilnacipran exposure by about 50%.
Levonorgestrel: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Levonorgestrel; Ethinyl Estradiol: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with adagrasib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with adagrasib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with adagrasib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Lithium: (Major) Concomitant use of adagrasib and lithium increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Lofexidine: (Major) Avoid concomitant use of adagrasib and lofexidine due to the potential for increased lofexidine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for lofexidine-related adverse effects, such as orthostatic hypotension and bradycardia, and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Lofexidine is a CYP2D6 substrate, adagrasib is a moderate CYP2D6 inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
Lomitapide: (Contraindicated) Concomitant use of adagrasib and lomitapide is contraindicated; if treatment with adagrasib is unavoidable, lomitapide should be stopped during treatment. Adagrasib is a strong CYP3A inhibitor and lomitapide is a CYP3A substrate. Coadministration with another strong CYP3A inhibitor increased lomitapide exposure approximately 27-fold.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and adagrasib is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. The exposure of adagrasib may also be increased. Lonafarnib is a CYP3A and CYP2C9 substrate and strong CYP3A inhibitor; adagrasib is a CYP3A substrate and strong CYP3A and moderate CYP2C9 inhibitor. Coadministration with another strong CYP3A inhibitor increased the exposure of lonafarnib by 425%.
Loperamide: (Major) Avoid concomitant use of adagrasib and loperamide due to the potential for increased loperamide exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for loperamide-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Loperamide is a CYP3A and P-gp substrate, adagrasib is a strong CYP3A and P-gp inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased loperamide exposure by 3.8-fold. Coadministration with another P-gp inhibitor increased loperamide exposure by 2- to 3-fold.
Loperamide; Simethicone: (Major) Avoid concomitant use of adagrasib and loperamide due to the potential for increased loperamide exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for loperamide-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Loperamide is a CYP3A and P-gp substrate, adagrasib is a strong CYP3A and P-gp inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased loperamide exposure by 3.8-fold. Coadministration with another P-gp inhibitor increased loperamide exposure by 2- to 3-fold.
Lopinavir; Ritonavir: (Contraindicated) Avoid concomitant use of adagrasib and lopinavir; ritonavir. Concomitant use may increase concentrations of both medications and result in additive risk for QT/QTc prolongation and torsade de pointes (TdP). The use of lopinavir; ritonavir with a CYP3A substrate that causes QT prolongation, such as adagrasib, is contraindicated per the manufacturer of lopinavir; ritonavir. If use is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation), monitor for lopinavir-related adverse effects, and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use before adagrasib steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib and lopinavir are CYP3A substrates and adagrasib and ritonavir are strong CYP3A inhibitors. Lopinavir; ritonavir and adagrasib have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state. (Moderate) Monitor for an increase in adagrasib-related adverse effects during concomitant use of ritonavir. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Lorlatinib: (Major) Avoid coadministration of lorlatinib with adagrasib due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If adagrasib is discontinued, resume the original dose of lorlatinib after 3 half-lives of adagrasib. Lorlatinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased lorlatinib exposure by 42%.
Losartan: (Moderate) Closely monitor blood pressure during coadministration of losartan and adagrasib; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; adagrasib is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure during coadministration of losartan and adagrasib; adjust the dose of losartan as clinically appropriate. Concomitant use may decrease exposure to the active metabolite of losartan and decrease losartan efficacy. Losartan is a CYP2C9 substrate; adagrasib is a moderate CYP2C9 inhibitor. Coadministration with a moderate CYP2C9 inhibitor in two pharmacokinetic studies with healthy volunteers decreased concentrations of the active metabolite of losartan by 30% to 56%.
Lovastatin: (Contraindicated) Coadministration of lovastatin and adagrasib is contraindicated due to the risk of elevated plasma concentrations of lovastatin leading to myopathy and rhabdomyolysis. Lovastatin is a sensitive CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. Coadministration with another strong CYP3A inhibitor increased lovastatin exposure by 11 to 36-fold.
Lumacaftor; Ivacaftor: (Major) Avoid concurrent use of adagrasib and lumacaftor; ivacaftor due to the risk of decreased adagrasib exposure which may reduce its efficacy. The exposure of lumacaftor; ivacaftor may also be increased; if concomitant use is necessary, a lumacaftor; ivacaftor dosage adjustment may be necessary. Adagrasib is a CYP3A substrate and strong CYP3A inhibitor and lumacaftor; ivacaftor is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A inhibitor increased ivacaftor exposure by 4.3-fold. (Major) If adagrasib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Lumacaftor; Ivacaftor: (Major) Avoid concurrent use of adagrasib and lumacaftor; ivacaftor due to the risk of decreased adagrasib exposure which may reduce its efficacy. The exposure of lumacaftor; ivacaftor may also be increased; if concomitant use is necessary, a lumacaftor; ivacaftor dosage adjustment may be necessary. Adagrasib is a CYP3A substrate and strong CYP3A inhibitor and lumacaftor; ivacaftor is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A inhibitor increased ivacaftor exposure by 4.3-fold.
Lumateperone: (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use with adagrasib is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased lumateperone exposure by approximately 4-fold.
Lurasidone: (Contraindicated) Coadministration of lurasidone with adagrasib is contraindicated due to increased plasma concentrations of lurasidone. Lurasidone is a sensitive CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased lurasidone exposure by 9-fold.
Lurbinectedin: (Major) Avoid concomitant use of lurbinectedin and adagrasib due to the risk of increased lurbinectedin exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of lurbinectedin by 50%. Lurbinectedin is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of lurbinectedin by 2.7-fold.
Macimorelin: (Major) Concomitant use of adagrasib and macimorelin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Macitentan: (Major) Avoid coadministration of macitentan with adagrasib due to the risk of increased macitentan exposure and adverse effects. Consider alternative treatment options for pulmonary hypertension if treatment with adagrasib is necessary. Macitentan is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased macitentan exposure by approximately 2-fold.
Macitentan; Tadalafil: (Major) Avoid coadministration of macitentan with adagrasib due to the risk of increased macitentan exposure and adverse effects. Consider alternative treatment options for pulmonary hypertension if treatment with adagrasib is necessary. Macitentan is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased macitentan exposure by approximately 2-fold. (Major) Avoid coadministration of tadalafil and adagrasib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of adagrasib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A. Potent inhibitors of CYP3A, such as adagrasib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Maprotiline: (Major) Avoid concomitant use of adagrasib and maprotiline due to the potential for increased maprotiline exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for maprotiline-related adverse effects; a dosage reduction may be required. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Maprotiline is a CYP2D6 substrate, adagrasib is a moderate CYP2D6 inhibitor, and both medications have been associated with QT interval prolongation.
Maraviroc: (Major) Reduce the dose of maraviroc when coadministration with adagrasib is necessary, regardless of whether the patient is receiving a concomitant strong CYP3A inducer. The effect of adagrasib on maraviroc exposure is expected to exceed that of the inducer and overall, increased maraviroc concentrations are expected. Coadministration of maraviroc with adagrasib is contraindicated in patients with CrCl less than 30 mL/min. Recommendations for reducing the maraviroc dose when administered with adagrasib (with or without a concomitant CYP3A inducer) are: adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily. Maraviroc is a sensitive CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. Coadministration with strong CYP3A inhibitors may result in increased maraviroc concentrations.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with adagrasib due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure. Mavacamten is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use with a strong CYP3A inhibitor is predicted to increase mavacamten overall exposure up to 130%.
Meclizine: (Moderate) Monitor for meclizine-related adverse effects, such as drowsiness and anticholinergic effects, when coadministered with adagrasib. Concomitant use may increase the exposure to meclizine. Meclizine is a CYP2D6 substrate and adagrasib is a CYP2D6 inhibitor.
Medroxyprogesterone: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Mefloquine: (Major) Avoid concomitant use of adagrasib and mefloquine due to the potential for increased mefloquine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for mefloquine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Mefloquine is a CYP3A and P-gp substrate, adagrasib is a strong CYP3A and P-gp inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased the exposure of mefloquine by 79%.
Meloxicam: (Moderate) Consider a meloxicam dose reduction and monitor for adverse reactions if coadministration with adagrasib is necessary. Concurrent use may increase meloxicam exposure. Meloxicam is a CYP2C9 substrate and adagrasib is a moderate CYP2C9 inhibitor.
Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. If adagrasib is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A and adagrasib is a strong CYP3A inhibitor. Concomitant use with adagrasib can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine.
Metformin; Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with adagrasib is necessary. Repaglinide is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with other strong CYP3A inhibitors increased repaglinide exposure by up to 1.5-fold.
Metformin; Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with adagrasib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the saxagliptin AUC up to 3.7-fold.
Methadone: (Major) Avoid concomitant use of adagrasib and methadone due to the potential for increased methadone exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Methadone is a CYP2C9, CYP2D6, and CYP3A substrate, adagrasib is a moderate CYP2C9, moderate CYP2D6, and strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Methohexital: (Major) Avoid concurrent use of adagrasib and barbiturates due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Methylergonovine: (Major) Avoid concomitant use of methylergonovine with adagrasib. Concomitant use may increase methylergonovine exposure and the risk for vasospasm which may lead to cerebral or peripheral ischemia. Methylergonovine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Methylprednisolone: (Moderate) Monitor for corticosteroid-related adverse events if methylprednisolone is used with adagrasib. Concurrent use may increase the exposure of methylprednisolone. Methylprednisolone is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Other strong CYP3A inhibitors have been reported to decrease the metabolism of certain corticosteroids by up to 60%.
Metoprolol: (Moderate) Monitor for metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with adagrasib. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and adagrasib is a CYP2D6 inhibitor.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with adagrasib. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and adagrasib is a CYP2D6 inhibitor.
Metronidazole: (Major) Concomitant use of adagrasib and metronidazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Mexiletine: (Moderate) Monitor for increased toxicity of mexiletine if coadministered with adagrasib. Coadministration may increase serum concentrations of mexiletine. Mexiletine is a CYP2D6 substrate and adagrasib is a moderate CYP2D6 inhibitor.
Midazolam: (Major) Avoid coadministration of midazolam with adagrasib. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and adagrasib is a CYP3A inhibitor. Concomitant use of adagrasib 400 mg twice daily has been observed to increase midazolam overall exposure by 21-fold and 600 mg twice daily is predicted to increase midazolam overall exposure by 31-fold.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and adagrasib due to the potential for increased midostaurin exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary, monitor patients for signs and symptoms of midostaurin toxicity (e.g., gastrointestinal toxicity, hematologic toxicity, bleeding, and infection), particularly during the first week of midostaurin therapy for systemic mastocytosis/mast cell leukemia and the first week of each cycle of midostaurin therapy for acute myeloid leukemia. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Midostaurin is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT prolongation. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A inhibitor.
Mifepristone: (Major) Avoid concomitant use of adagrasib and mifepristone especially during the first 8 days of adagrasib therapy initiation. The concentrations of both medications may be increased and there is an additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, a mifepristone dosage adjustment may be required if it is being used in the treatment of Cushing's syndrome. Limit mifepristone to a maximum dosage of 900 mg per day. In a patient already receiving adagrasib, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with adagrasib is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with adagrasib is initiated in a patient already receiving mifepristone 600 mg, reduce dose of mifepristone to 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with adagrasib is initiated in a patient receiving already receiving 900 mg, reduce dose of mifepristone to 600 mg and titrate to a maximum of 900 mg if clinically indicated. In a patient receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Mifepristone and adagrasib are CYP3A substrates and strong CYP3A inhibitors and both medications have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Mirtazapine: (Major) Avoid concomitant use of adagrasib and mirtazapine due to the potential for increased mirtazapine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for mirtazapine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Mirtazapine is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Mirvetuximab Soravtansine: (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of adagrasib is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure.
Mitapivat: (Major) Avoid coadministration of mitapivat with adagrasib due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold.
Mitotane: (Major) Avoid concurrent use of adagrasib and mitotane due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and adagrasib due to the potential for increased mobocertinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Mobocertinib is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Use of a strong CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%.
Modafinil: (Moderate) Monitor for an increase in modafinil-related adverse reactions if coadministration with adagrasib is necessary. Modafinil has multiple pathways for metabolism including non-CYP-related pathways; however, due to partial involvement of the CYP3A enzymes, concomitant use of strong CYP3A inhibitors such as adagrasib could increase plasma concentrations of modafinil.
Mometasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of mometasone with adagrasib is necessary, due to increased mometasone exposure; Cushing's syndrome and adrenal suppression could potentially occur with long-term use. Mometasone is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with adagrasib is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and adagrasib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with adagrasib is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and adagrasib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Moxifloxacin: (Major) Concomitant use of adagrasib and moxifloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Naldemedine: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with adagrasib. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a CYP3A and P-gp substrate; adagrasib is a strong CYP3A and P-gp inhibitor.
Naloxegol: (Contraindicated) Concomitant use of naloxegol with adagrasib is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A inhibitors, such as adagrasib, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with adagrasib is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. In vitro, coadministration with both strong and moderate CYP3A inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and adagrasib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Naproxen; Esomeprazole: (Moderate) Monitor for esomeprazole-related adverse effects during coadministration with adagrasib. Concurrent use may increase esomeprazole exposure. Esomeprazole is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Nateglinide: (Moderate) Monitor for an increase in nateglinide-related adverse effects, such as hypoglycemia, if concomitant use with adagrasib is necessary; a nateglinide dosage reduction may be required. Concomitant use may increase nateglinide exposure. Nateglinide is a CYP2C9 substrate and adagrasib is a moderate CYP2C9 inhibitor. Concomitant use with another moderate CYP2C9 inhibitor increased nateglinide overall exposure by 48%.
Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with adagrasib; adjust the nebivolol dose according to blood pressure response. Concomitant use may increase the exposure of nebivolol. Nebivolol is a CYP2D6 substrate and adagrasib is a moderate CYP2D6 inhibitor.
Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with adagrasib; adjust the nebivolol dose according to blood pressure response. Concomitant use may increase the exposure of nebivolol. Nebivolol is a CYP2D6 substrate and adagrasib is a moderate CYP2D6 inhibitor.
Nefazodone: (Moderate) Monitor for an increase in adagrasib-related adverse effects during concomitant use of nefazodone. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Nelfinavir: (Moderate) Monitor for an increase in adverse effects from both drugs during concomitant use of adagrasib and nelfinavir. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib and nelfinavir are both CYP3A substrates and strong CYP3A inhibitors. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state. Coadministration with another strong CYP3A inhibitor increased the exposure of nelfinavir by 35%.
Neratinib: (Major) Avoid concomitant use of adagrasib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A may also increase neratinib concentrations.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Monitor for an increase in netupitant-related adverse reactions if coadministration with adagrasib is necessary. Netupitant is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased netupitant exposure by 140%; however, no dosage adjustment is necessary.
Nevirapine: (Moderate) Monitor for an increase in nevirapine-related adverse reactions if coadministration with adagrasib is necessary. Nevirapine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor increased nevirapine exposure by 100%; concomitant use with a strong CYP3A inhibitor may also increase nevirapine exposure.
NIFEdipine: (Moderate) Careful monitoring and dose adjustment of nifedipine may be necessary if administered with adagrasib as nifedipine exposure and adverse effects may be increased. Consider initiating nifedipine at the lowest dose. Nifedipine is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor.
Nilotinib: (Major) Avoid the concomitant use of nilotinib and adagrasib due to the potential for increased nilotinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is required, reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. Additionally, consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. If adagrasib is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A, adagrasib is a strong inhibitor of CYP3A, and both medications have been associated with QT interval prolongation.
Nimodipine: (Major) Avoid coadministration of nimodipine with adagrasib due to the risk of significant hypotension. If concomitant use is unavoidable, monitor blood pressure and reduce the dose of nimodipine as clinically appropriate. Nimodipine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for an increase in adagrasib-related adverse effects during concomitant use of ritonavir. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Nirogacestat: (Major) Avoid concomitant use of nirogacestat and adagrasib due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Nirogacestat is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with adagrasib due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and adagrasib is a CYP3A inhibitor. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Norethindrone: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Norethindrone; Ethinyl Estradiol: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Norgestimate; Ethinyl Estradiol: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Norgestrel: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Nortriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with adagrasib is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; adagrasib is a CYP2D6 inhibitor.
Ofloxacin: (Major) Concomitant use of adagrasib and ofloxacin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine: (Major) Concomitant use of adagrasib and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine; Fluoxetine: (Major) Avoid concomitant use of adagrasib and fluoxetine due to the potential for increased fluoxetine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for fluoxetine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Fluoxetine is a CYP2D6 substrate, adagrasib is a moderate CYP2D6 inhibitor, and both medications have been associated with QT interval prolongation. (Major) Concomitant use of adagrasib and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olanzapine; Samidorphan: (Major) Concomitant use of adagrasib and olanzapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Olaparib: (Major) Avoid coadministration of olaparib with adagrasib due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 100 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after adagrasib is discontinued. Olaparib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor; concomitant use may increase olaparib exposure. Coadministration with another strong CYP3A inhibitor increased the olaparib Cmax by 42% and the AUC by 170%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and adagrasib is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and adagrasib may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects; these effects may be more pronounced with adagrasib as it can inhibit multiple CYP enzymes. If adagrasib is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A and CYP2D6 substrate and adagrasib is a strong CYP3A inhibitor and moderate CYP2D6 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with adagrasib is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Olopatadine; Mometasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of mometasone with adagrasib is necessary, due to increased mometasone exposure; Cushing's syndrome and adrenal suppression could potentially occur with long-term use. Mometasone is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and adagrasib. If concomitant use is necessary, decrease omaveloxolone dose to 50 mg once daily. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased omaveloxolone overall exposure by 4-fold.
Omeprazole: (Moderate) Monitor for omeprazole-related adverse effects during coadministration with adagrasib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Monitor for an increase in rifabutin-related adverse reactions if coadministration with adagrasib is necessary; in some cases, the dose of rifabutin may need to be decreased. Rifabutin is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with CYP3A inhibitors may significantly increase the plasma concentration of rifabutin. (Moderate) Monitor for omeprazole-related adverse effects during coadministration with adagrasib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Omeprazole; Sodium Bicarbonate: (Moderate) Monitor for omeprazole-related adverse effects during coadministration with adagrasib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Ondansetron: (Major) Concomitant use of adagrasib and ondansetron increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose.
Osilodrostat: (Major) Avoid concomitant use of adagrasib and osilodrostat due to the potential for increased osilodrostat exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, reduce the dose of osilodrostat by half during coadministration of adagrasib and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Osilodrostat is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Osimertinib: (Major) Concomitant use of adagrasib and osimertinib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ospemifene: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with adagrasib is necessary. Ospemifene is a CYP2C9 and CYP3A substrate and adagrasib is a dual moderate CYP2C9 and strong CYP3A inhibitor. Coadministration of another dual CYP2C9/CYP3A inhibitor increased ospemifene systemic exposure by 2.7-fold.
Oxaliplatin: (Major) Concomitant use of adagrasib and oxaliplatin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Oxybutynin: (Moderate) Monitor for an increase in oxybutynin-related adverse reactions if coadministration with adagrasib is necessary. Oxybutynin is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased mean oxybutynin plasma concentrations by approximately 2-fold.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. If adagrasib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with strong CYP3A inhibitors like adagrasib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If adagrasib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Ozanimod: (Major) Concomitant use of adagrasib and ozanimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Ozanimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of paclitaxel with adagrasib is necessary due to the risk of increased plasma concentrations of paclitaxel. Paclitaxel is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. In vitro, coadministration with both strong and moderate CYP3A inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A inhibitors.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with adagrasib is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Concomitant use also increases the risk for QT/QTc prolongation and torsade de pointes (TdP). Pacritinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Both medications have been associated with QT interval prolongation.
Palbociclib: (Major) Avoid coadministration of palbociclib with adagrasib; significantly increased plasma exposure of palbociclib may occur. If concomitant use is unavoidable, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If adagrasib is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of adagrasib) to the dose used before initiation of adagrasib. Palbociclib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the exposure of palbociclib by 87%.
Paliperidone: (Major) Concomitant use of adagrasib and paliperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Palovarotene: (Major) Avoid concomitant use of palovarotene and adagrasib due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. Palovarotene is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased palovarotene overall exposure by 3-fold.
Panobinostat: (Major) Avoid concomitant use of adagrasib and panobinostat due to the potential for increased panobinostat exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, reduce the starting dose of panobinostat to 10 mg and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Panobinostat is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration of another strong CYP3A inhibitor increased the AUC of panobinostat by 73%.
Paricalcitol: (Moderate) Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with both paricalcitol and adagrasib, or during periods of dose titration. If hypercalcemia occurs, the dose of paricalcitol should be reduced or withheld until these parameters are normalized. Paricalcitol is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor approximately doubled the exposure of paricalcitol.
Paroxetine: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with adagrasib is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and adagrasib is a moderate CYP2D6 inhibitor.
Pasireotide: (Major) Concomitant use of adagrasib and pasireotide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Pazopanib: (Major) Avoid coadministration of pazopanib and adagrasib due to the potential for increased pazopanib exposure; there is also an additive risk for QT/QTc prolongation and torsade de pointes (TdP). Pazopanib is a CYP3A and P-gp substrate, adagrasib is a strong CYP3A and P-gp inhibitor, and both medications have been associated with QT interval prolongation. Concurrent use of another strong CYP3A inhibitor increased the Cmax and AUC of pazopanib by 1.5-fold and 1.7-fold, respectively.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and adagrasib due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If adagrasib is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of adagrasib. Pemigatinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased pemigatinib exposure by 88%.
Pentamidine: (Major) Concomitant use of adagrasib and systemic pentamidine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Pentobarbital: (Major) Avoid concurrent use of adagrasib and barbiturates due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with adagrasib is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Perphenazine: (Minor) QT/QTc prolongation can occur with concomitant use of adagrasib and perphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Perphenazine; Amitriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with adagrasib is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; adagrasib is a CYP2D6 inhibitor. (Minor) QT/QTc prolongation can occur with concomitant use of adagrasib and perphenazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and adagrasib due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If adagrasib is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of adagrasib. Pexidartinib is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased pexidartinib exposure by 70%.
Phenobarbital: (Major) Avoid concurrent use of adagrasib and barbiturates due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concurrent use of adagrasib and barbiturates due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Phenytoin: (Major) Avoid concurrent use of adagrasib and phenytoin due to the risk of decreased adagrasib exposure which may reduce its efficacy. The exposure of phenytoin may also be increased. Adagrasib is a CYP3A substrate and moderate CYP2C9 inhibitor and phenytoin is a CYP2C9 substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Pimavanserin: (Major) Avoid concomitant use of adagrasib and pimavanserin due to the potential for increased pimavanserin exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, reduce pimavanserin to 10 mg PO once daily and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Pimavanserin is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. In drug interaction studies, coadministration with a strong CYP3A inhibitor increased exposure to pimavanserin by 3-fold.
Pimozide: (Contraindicated) Concurrent use of pimozide and adagrasib is contraindicated. Coadministration may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Additive QT prolongation may also occur. Pimozide is a CYP3A and CYP2D6 substrate and adagrasib is a strong CYP3A and moderate CYP2D6 inhibitor.
Pioglitazone; Glimepiride: (Moderate) Monitor for an increase in glimepiride-related adverse reactions, such as hypoglycemia, if coadministration with adagrasib is necessary. Concomitant use may increase glimepiride exposure. Glimepiride is a CYP2C9 substrate; adagrasib is a moderate CYP2C9 inhibitor.
Pirtobrutinib: (Major) Avoid concomitant use of pirtobrutinib and adagrasib due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of adagrasib use. Resume the previous dose of pirtobrutinib after adagrasib is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Pitavastatin: (Moderate) Monitor for an increase in pitavastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with adagrasib is necessary. Concomitant use may increase pitavastatin exposure. Pitavastatin is a P-gp substrate; adagrasib is a P-gp inhibitor.
Pitolisant: (Major) Concomitant use of adagrasib and pitolisant increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Polatuzumab Vedotin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of adagrasib due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A and adagrasib is a strong CYP3A inhibitor. Strong CYP3A inhibitors are predicted to increase the exposure of MMAE by 45%.
Ponatinib: (Major) Avoid coadministration of ponatinib and adagrasib due to the potential for increased ponatinib exposure. If concurrent use is necessary, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of adagrasib and consider alternative therapy. After adagrasib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting adagrasib. Ponatinib is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the ponatinib AUC by 78%.
Ponesimod: (Major) Concomitant use of adagrasib and ponesimod increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Ponesimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Posaconazole: (Contraindicated) Avoid concomitant use of adagrasib and posaconazole. Concomitant use may increase concentrations of both medications and result in additive risk for QT/QTc prolongation and torsade de pointes (TdP). The use of posaconazole with a CYP3A substrate that causes QT prolongation, such as adagrasib, is contraindicated per the manufacturer of posaconazole. If use is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation), monitor for posaconazole-related adverse effects, and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use before adagrasib steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and P-gp inhibitor, posaconazole is a P-gp substrate and strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Pralsetinib: (Major) Avoid concomitant use of adagrasib and pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of pralsetinib to 200 mg once daily for patients taking a daily dose of 400 mg or 300 mg, and to 100 mg once daily for patients taking a daily dose of 200 mg. Pralsetinib is a CYP3A and P-gp substrate and adagrasib is a combined strong CYP3A and P-gp inhibitor. Coadministration with a combined strong CYP3A and P-gp inhibitor is predicted to increase the overall exposure of pralsetinib by 251%.
Prednisolone: (Moderate) Monitor for corticosteroid-related adverse events if prednisolone is used with adagrasib. Concurrent use may increase the exposure of prednisolone. Prednisolone is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Other strong CYP3A inhibitors have been reported to decrease the metabolism of certain corticosteroids by up to 60%.
Prednisone: (Moderate) Monitor for corticosteroid-related adverse events if prednisone is used with adagrasib. Concurrent use may increase the exposure of prednisone. Prednisone is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Other strong CYP3A inhibitors have been reported to decrease the metabolism of certain corticosteroids by up to 60%.
Primaquine: (Major) Concomitant use of adagrasib and primaquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Primidone: (Major) Avoid concurrent use of adagrasib and barbiturates due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and adagrasib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and adagrasib is a dual strong CYP3A and P-gp inhibitor. Concomitant use with other dual strong CYP3A and P-gp inhibitors has been observed to increase colchicine overall exposure by 3- to 4-fold.
Procainamide: (Major) Concomitant use of adagrasib and procainamide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Prochlorperazine: (Minor) QT/QTc prolongation can occur with concomitant use of adagrasib and prochlorperazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Progesterone: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Progestins: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Promethazine: (Major) Concomitant use of adagrasib and promethazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Dextromethorphan: (Major) Concomitant use of adagrasib and promethazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Promethazine; Phenylephrine: (Major) Concomitant use of adagrasib and promethazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Propafenone: (Major) Avoid concurrent use of propafenone and adagrasib; concurrent use may increase plasma concentrations of propafenone and result in additive risk for QT/QTc prolongation and torsade de pointes (TdP). Propafenone is a CYP2D6 and CYP3A substrate, adagrasib is a moderate CYP2D6 inhibitor and a strong 3A inhibitor, and both medications have been associated with QT interval prolongation.
Propranolol: (Moderate) Monitor for increased propranolol adverse reactions, including bradycardia and hypotension, during coadministration of adagrasib as concurrent use may increase propranolol exposure. Propranolol is a CYP2D6 substrate and adagrasib is moderate CYP2D6 inhibitor.
Protriptyline: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with adagrasib is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; adagrasib is a CYP2D6 inhibitor.
Quazepam: (Moderate) Monitor for an increase in quazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with adagrasib is necessary; reduce the dose of quazepam if clinically appropriate. Concurrent use may increase the concentrations of quazepam. Quazepam is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Quetiapine: (Major) Avoid concomitant use of adagrasib and quetiapine due to the potential for increased quetiapine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, reduce quetiapine dose to one sixth and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Quetiapine is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased the exposure of quetiapine by approximately 6-fold.
Quinidine: (Major) Avoid concomitant use of adagrasib and quinidine due to the potential for increased quinidine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for quinidine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Quinidine is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Quinine: (Major) Avoid concomitant use of adagrasib and quinine due to the potential for increased quinine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for quinine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Quinine is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration of another strong CYP3A inhibitor increased the exposure of quinine by 45%.
Quizartinib: (Major) Avoid concomitant use of adagrasib with quizartinib due to the risk of increased quizartinib exposure which may increase the risk of adverse reactions. Concomitant use may also increase the risk for torsade de pointes (TdP) and QT/QTc prolongation. If concomitant use is necessary, reduce the dose of quizartinib to 26.5 mg for patients taking a daily dose of 53 mg, and to 17.7 mg for patients taking a daily dose of 35.4 mg or 26.5 mg; interrupt quizartinib therapy for the duration of the strong CYP3A inhibitor use for patients already taking a daily dose of 17.7 mg. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Quizartinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of quizartinib by 94%.
Ramelteon: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with adagrasib is necessary. Ramelteon is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ramelteon exposure by 84%.
Ranolazine: (Contraindicated) Coadministration of ranolazine with adagrasib is contraindicated as concurrent use may increase ranolazine exposure. Concomitant use also increases the risk for QT/QTc prolongation and torsade de pointes (TdP). Ranolazine is a CYP3A and P-gp substrate, adagrasib is a strong CYP3A and P-gp inhibitor, and both medications have been associated with QT interval prolongation. Coadministration of another strong CYP3A inhibitor increased ranolazine exposure by 220%.
Regorafenib: (Major) Avoid coadministration of regorafenib with adagrasib due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
Relugolix: (Major) Avoid concomitant use of adagrasib and relugolix due to the potential for increased relugolix exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, administer adagrasib at least 6 hours after relugolix and monitor for adverse reactions. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Relugolix is a P-gp substrate, adagrasib is a P-gp inhibitor, and both medications have been associated with QT interval prolongation.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of adagrasib and relugolix due to the potential for increased relugolix exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, administer adagrasib at least 6 hours after relugolix and monitor for adverse reactions. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Relugolix is a P-gp substrate, adagrasib is a P-gp inhibitor, and both medications have been associated with QT interval prolongation. (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with adagrasib is necessary. Repaglinide is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with other strong CYP3A inhibitors increased repaglinide exposure by up to 1.5-fold.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with adagrasib due to increased repotrectinib exposure which may increase the risk for repotrectinib-related adverse effects. Repotrectinib is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. Coadministration with another strong CYP3A and P-gp inhibitor increased repotrectinib exposure by 5.9-fold.
Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A inhibitors, such as adagrasib, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A substrate.
Ribociclib: (Major) Avoid coadministration of ribociclib with adagrasib due to the potential for increased exposure to both drugs and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation), reduce the dose of ribociclib to 400 mg once daily, and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Ribociclib and adagrasib are both CYP3A substrates and strong CYP3A inhibitors and both medications have been associated with QT interval prolongation. Coadministration with a strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with adagrasib due to the potential for increased exposure to both drugs and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation), reduce the dose of ribociclib to 400 mg once daily, and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Ribociclib and adagrasib are both CYP3A substrates and strong CYP3A inhibitors and both medications have been associated with QT interval prolongation. Coadministration with a strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Rifabutin: (Moderate) Monitor for an increase in rifabutin-related adverse reactions if coadministration with adagrasib is necessary; in some cases, the dose of rifabutin may need to be decreased. Rifabutin is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with CYP3A inhibitors may significantly increase the plasma concentration of rifabutin.
Rifampin: (Major) Avoid concurrent use of adagrasib and rifampin due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use with rifampin reduced adagrasib exposure by more than 66%.
Rifapentine: (Major) Avoid concurrent use of adagrasib and rifapentine due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and rifapentine is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with adagrasib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and adagrasib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rilpivirine: (Major) Avoid concomitant use of adagrasib and rilpivirine due to the potential for increased rilpivirine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for rilpivirine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Rilpivirine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Both medications have been associated with QT interval prolongation, however, the degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Rimegepant: (Major) Avoid coadministration of rimegepant with adagrasib; concurrent use may significantly increase rimegepant exposure. Rimegepant is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. Coadministration of rimegepant with another strong CYP3A inhibitor increased rimegepant exposure by 4-fold.
Ripretinib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with adagrasib. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ripretinib and DP-5439 exposure by 99%.
Risperidone: (Major) Concomitant use of adagrasib and risperidone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Ritonavir: (Moderate) Monitor for an increase in adagrasib-related adverse effects during concomitant use of ritonavir. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with adagrasib is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the exposure of roflumilast by 99%.
Romidepsin: (Major) Avoid concomitant use of adagrasib and romidepsin due to the potential for increased romidepsin exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for romidepsin-related adverse effects and follow the dose modifications for toxicity as appropriate. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Romidepsin is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. In a pharmacokinetic drug interaction trial a strong CYP3A inhibitor increased romidepsin AUC by approximately 25%.
Ruxolitinib: (Major) Reduce the ruxolitinib dosage when coadministered with adagrasib in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust ruxolitinib dosage for adverse reactions. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Avoid the use of adagrasib in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily; alternatively, ruxolitinib therapy may be interrupted for the duration of adagrasib use. Ruxolitinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Salmeterol: (Major) Avoid concomitant use of salmeterol with adagrasib. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
Saquinavir: (Contraindicated) Avoid concomitant use of adagrasib and saquinavir. Concomitant use may increase concentrations of both medications and result in additive risk for QT/QTc prolongation and torsade de pointes (TdP). The use of saquinavir with a drug that increases saquinavir concentrations and prolongs the QT interval, such as adagrasib, is contraindicated per the manufacturer of saquinavir. If use is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation), monitor for saquinavir-related adverse effects, and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use before adagrasib steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and strong CYP3A and P-gp inhibitor, saquinavir is a CYP3A and P-gp substrate and strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with adagrasib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the saxagliptin AUC up to 3.7-fold.
Secobarbital: (Major) Avoid concurrent use of adagrasib and barbiturates due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and barbiturates is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Segesterone Acetate; Ethinyl Estradiol: (Moderate) Use caution if coadministration of adagrasib with progestins is necessary, as the systemic exposure of progestins may be increased resulting in an increase in treatment-related adverse reactions. Progestins are metabolized primarily by hydroxylation via a CYP3A; adagrasib is a strong CYP3A inhibitor.
Selpercatinib: (Major) Avoid concomitant use of adagrasib and selpercatinib due to the potential for increased selpercatinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary, reduce the dose of selpercatinib to 40 mg PO twice daily if original dose was 120 mg twice daily, and to 80 mg PO twice daily if original dose was 160 mg twice daily. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Selpercatinib is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased selpercatinib exposure by 133%.
Selumetinib: (Major) Avoid coadministration of selumetinib and adagrasib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If adagrasib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of adagrasib. Selumetinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased selumetinib exposure by 49%.
Sertraline: (Major) Concomitant use of adagrasib and sertraline increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Concomitant use of adagrasib and halogenated anesthetics increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sildenafil: (Major) Coadministration with adagrasib is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving adagrasib. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Adagrasib is a strong CYP3A inhibitor and sildenafil is a sensitive CYP3A substrate. Coadministration of other strong CYP3A inhibitors increased the sildenafil AUC between 3- and 11-fold.
Silodosin: (Contraindicated) Concurrent use of silodosin and adagrasib is contraindicated due to increased plasma concentrations of silodosin resulting in an increase of treatment-related adverse reactions. Silodosin is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. Coadministration with another strong CYP3A inhibitor increased silodosin exposure by 2.9-fold to 3.2-fold.
Simvastatin: (Contraindicated) Concurrent use of simvastatin and adagrasib is contraindicated due to an increased risk of developing myopathy, rhabdomyolysis, and acute renal failure. Concomitant use my increase simvastatin exposure. Simvastatin is a sensitive CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Siponimod: (Major) Avoid concomitant use of adagrasib and siponimod due to the potential for increased siponimod exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). Siponimod is a CYP2C9 and CYP3A substrate, adagrasib is a dual moderate CYP2C9 and strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Sirolimus: (Major) Avoid concomitant use of sirolimus and adagrasib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
Sodium Stibogluconate: (Major) Concomitant use of adagrasib and sodium stibogluconate increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Solifenacin: (Major) Avoid concomitant use of adagrasib and solifenacin due to the potential for increased solifenacin exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, do not exceed a dose of 5 mg per day of solifenacin and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Solifenacin is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration of another strong CYP3A inhibitor increased solifenacin exposure by 2.7-fold.
Sonidegib: (Major) Avoid coadministration of sonidegib with adagrasib due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased sonidegib exposure by 2.2-fold.
Sorafenib: (Major) Concomitant use of adagrasib and sorafenib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sotalol: (Major) Concomitant use of adagrasib and sotalol increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Sparsentan: (Major) Avoid concomitant use of sparsentan and adagrasib. Concomitant use may increase sparsentan exposure and the risk for sparsentan-related adverse effects. Sparsentan is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased sparsentan overall exposure by 174%.
St. John's Wort, Hypericum perforatum: (Major) Avoid concurrent use of adagrasib and St. John's wort due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if adagrasib must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of adagrasib is necessary. If adagrasib is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A substrate, and coadministration with a strong CYP3A inhibitor like adagrasib can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If adagrasib is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sunitinib: (Major) Avoid concomitant use of adagrasib and sunitinib due to the potential for increased sunitinib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, consider reducing the daily dose of sunitinib to a minimum of 37.5 mg for patients with GIST or RCC, and to a minimum of 25 mg for patients with pNET. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Sunitinib is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased exposure to sunitinib and its primary active metabolite by 51%.
Suvorexant: (Major) Coadministration of suvorexant and adagrasib is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the suvorexant AUC by 2.8-fold.
Tacrolimus: (Major) Avoid concomitant use of adagrasib and tacrolimus due to the potential for increased tacrolimus exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, decrease tacrolimus dose and adjust dose based on tacrolimus serum concentrations. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Tadalafil: (Major) Avoid coadministration of tadalafil and adagrasib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of adagrasib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A. Potent inhibitors of CYP3A, such as adagrasib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with adagrasib is necessary. Talazoparib is a P-gp substrate and adagrasib is a P-gp inhibitor.
Tamoxifen: (Major) Concomitant use of adagrasib and tamoxifen increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tamsulosin: (Major) Concurrent use of tamsulosin and adagrasib is not recommended due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is a CYP3A and CYP2D6 substrate and adagrasib is a strong CYP3A and moderate CYP2D6 inhibitor. Concomitant treatment with another strong CYP3A inhibitor increased the AUC of tamsulosin by 2.8-fold.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with adagrasib as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Tazemetostat is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration of a moderate CYP3A inhibitor increased tazemetostat exposure by 3.1-fold.
Telavancin: (Major) Concomitant use of adagrasib and telavancin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with adagrasib is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Temsirolimus: (Major) Avoid coadministration of temsirolimus and adagrasib due to the risk of increased temsirolimus exposure resulting in an increased risk of adverse reactions. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. If adagrasib is discontinued, resume the original temsirolimus dose after a washout period of approximately 1 week. Temsirolimus is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. Coadministration with another strong CYP3A inhibitor did not have a significant effect on temsirolimus exposure, but increased the exposure of sirolimus (the primary and active metabolite) by 3.1-fold.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with adagrasib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and adagrasib is a P-gp inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with adagrasib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and adagrasib is a P-gp inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with adagrasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp substrate and adagrasib is a P-gp inhibitor.
Tetrabenazine: (Major) Concomitant use of adagrasib and tetrabenazine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tezacaftor; Ivacaftor: (Major) If adagrasib and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with adagrasib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, give one tezacaftor/ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Thioridazine: (Contraindicated) Coadministration of thioridazine and adagrasib is contraindicated due to the potential for increased thioridazine exposure. Concomitant use may also result in additive risk for QT/QTc prolongation and torsade de pointes (TdP). Thioridazine is a CYP2D6 substrate, adagrasib is a moderate CYP2D6 inhibitor, and both medications have been associated with QT interval prolongation.
Thiotepa: (Major) Avoid the concomitant use of thiotepa and adagrasib if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A to the active metabolite, TEPA; adagrasib is a strong CYP3A inhibitor.
Ticagrelor: (Major) Avoid coadministration of ticagrelor with adagrasib due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. Coadministration with another strong CYP3A inhibitor increased ticagrelor exposure by 7.32-fold.
Tinidazole: (Moderate) Monitor for an increase in tinidazole-related adverse reactions if coadministration with adagrasib is necessary. Concurrent use may increase the exposure of tinidazole. Tinidazole is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Tipranavir: (Moderate) Monitor for an increase in adverse effects from both drugs during concomitant use of adagrasib and tipranavir. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and strong CYP3A and P-gp inhibitor; tipranavir is a CYP3A and P-gp substrate and strong CYP3A inhibitor. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Tisotumab Vedotin: (Moderate) Closely monitor for tisotumab vedotin-related adverse reactions if concomitant use with adagrasib is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with adagrasib. In patients receiving tofacitinib 5 mg twice daily, reduce to 5 mg once daily; in patients receiving tofacitinib 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving tofacitinib extended-release 11 mg once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased tofacitinib exposure by 2-fold.
Tolterodine: (Major) Avoid concomitant use of adagrasib and tolterodine due to the potential for increased tolterodine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Tolterodine is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. In CYP2D6 poor metabolizers, the CYP3A pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A inhibitors. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Tolvaptan: (Contraindicated) The concomitant use of tolvaptan and adagrasib is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A substrate; adagrasib is a strong inhibitor of CYP3A. Coadministration of another strong CYP3A inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A inhibitors.
Topotecan: (Major) Avoid coadministration of adagrasib with oral topotecan due to increased topotecan exposure; adagrasib may be administered with intravenous topotecan. Coadministration increases the risk of topotecan-related adverse reactions. Oral topotecan is a substrate of the P-gp and adagrasib is a P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Toremifene: (Major) Avoid concomitant use of adagrasib and toremifene due to the potential for increased toremifene exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Toremifene is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
Trabectedin: (Major) Avoid the concomitant use of trabectedin with adagrasib due to the risk of increased trabectedin exposure. If short-term adagrasib (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Tramadol: (Moderate) Concurrent use of tramadol with adagrasib may produce unpredictable effects, including prolonged opioid-related adverse reactions, such as fatal respiratory depression, a withdrawal syndrome in those with physical dependence to opioid agonists, seizures, or serotonin syndrome. Consider dose adjustments of tramadol until stable drug effects are achieved. Monitor patients closely for respiratory depression and sedation at frequent intervals. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Tramadol is primarily metabolized by CYP2D6 to the active metabolite M1, and by CYP3A; adagrasib is a dual moderate CYP2D6 and strong CYP3A inhibitor. CYP3A inhibitors may increase tramadol-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Tramadol; Acetaminophen: (Moderate) Concurrent use of tramadol with adagrasib may produce unpredictable effects, including prolonged opioid-related adverse reactions, such as fatal respiratory depression, a withdrawal syndrome in those with physical dependence to opioid agonists, seizures, or serotonin syndrome. Consider dose adjustments of tramadol until stable drug effects are achieved. Monitor patients closely for respiratory depression and sedation at frequent intervals. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Tramadol is primarily metabolized by CYP2D6 to the active metabolite M1, and by CYP3A; adagrasib is a dual moderate CYP2D6 and strong CYP3A inhibitor. CYP3A inhibitors may increase tramadol-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with adagrasib. Coadministration may increase the exposure of verapamil. Adagrasib is a strong inhibitor of CYP3A; verapamil is a substrate of CYP3A.
Trazodone: (Major) Avoid concomitant use of adagrasib and trazodone due to the potential for increased trazodone exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, consider a reduced dose of trazodone based on tolerability. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Trazodone is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation.
Triamcinolone: (Moderate) Monitor for an increase in triamcinolone-related adverse effects, such as fluid retention, electrolyte disturbances, and adrenal suppression, if concomitant use of adagrasib is necessary. Concomitant use may increase triamcinolone exposure. Triamcinolone is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Other strong CYP3A inhibitors have decreased corticosteroid metabolism by up to 60%.
Triazolam: (Contraindicated) Concomitant use of adagrasib with triazolam is contraindicated due to the risk of serious adverse events, such as prolonged hypnotic and/or sedative effects. Triazolam is a sensitive CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Consider safer alternatives if a benzodiazepine must be administered in combination with adagrasib. Benzodiazepines not metabolized by the CYP3A enzyme (e.g., lorazepam, oxazepam) are less likely to be affected by strong CYP3A inhibitors.
Triclabendazole: (Major) Concomitant use of adagrasib and triclabendazole increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tricyclic antidepressants: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with adagrasib is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; adagrasib is a CYP2D6 inhibitor.
Trifluoperazine: (Minor) QT/QTc prolongation can occur with concomitant use of adagrasib and trifluoperazine although the risk of developing torsade de pointes (TdP) is low. Additional steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, may be considered in patients with additional risk factors for TdP.
Trimipramine: (Moderate) Monitor for an increase in tricyclic antidepressant (TCA)-related adverse reactions if coadministration with adagrasib is necessary; a dose reduction of TCA may be necessary. Concurrent use may increase the exposure of TCAs which are CYP2D6 substrates; adagrasib is a CYP2D6 inhibitor.
Triptorelin: (Major) Concomitant use of adagrasib and androgen deprivation therapy (i.e., triptorelin) increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Tucatinib: (Moderate) Monitor for an increase in adagrasib-related adverse effects during concomitant use of tucatinib. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Ubrogepant: (Contraindicated) Coadministration of ubrogepant and adagrasib is contraindicated as concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. Coadministration with another strong CYP3A inhibitor resulted in a 9.7-fold increase in the exposure of ubrogepant.
Ulipristal: (Minor) Concomitant use of ulipristal and adagrasib may increase the plasma concentration of ulipristal resulting in an increased risk for ulipristal-related adverse events; however, this is not likely to be significant for single-dose emergency contraceptive use. Ulipristal is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ulipristal overall exposure by 5.9-fold and increased the overall exposure if ulipristal's active metabolite, monodemethyl-ulipristal acetate, by 2.4-fold.
Umeclidinium; Vilanterol: (Moderate) Monitor for an increase in vilanterol-related adverse effects if coadministered with adagrasib. Coadministration may increase vilanterol exposure. Vilanterol is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor significantly increased systemic exposure to vilanterol.
Upadacitinib: (Major) During concomitant use of upadacitinib and adagrasib reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Valbenazine: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with adagrasib is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Vamorolone: (Major) Decrease the vamorolone dose to 4 mg/kg once daily (max: 200 mg) and monitor for adverse effects if concomitant use with adagrasib is necessary. Concomitant use may increase vamorolone exposure and the risk for vamorolone-related adverse effects. Vamorolone is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased vamorolone overall exposure by 44%.
Vandetanib: (Major) Concomitant use of adagrasib and vandetanib increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Vardenafil: (Major) Avoid concomitant use of adagrasib and vardenafil due to the potential for increased vardenafil exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If concomitant use is necessary, use vardenafil oral tablets instead of orally disintegrating tablets and do not exceed a single dose of 2.5 mg per 24-hour period. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Vardenafil is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with other strong CYP3A inhibitors increased the AUC of vardenafil by 10- to 16-fold.
Vemurafenib: (Major) Avoid concomitant use of adagrasib and vemurafenib due to the potential for increased vemurafenib exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Additionally, consider taking steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Vemurafenib is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased the exposure of vemurafenib by 40%.
Venetoclax: (Major) Coadministration of adagrasib with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of adagrasib. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. Coadministration with strong CYP3A inhibitors increased the venetoclax AUC by 90% to 690% and coadministration with a single dose of a P-gp inhibitor increased venetoclax exposure by 78%.
Venlafaxine: (Major) Concomitant use of adagrasib and venlafaxine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Verapamil: (Moderate) Monitor blood pressure and heart rate during coadministration of verapamil with adagrasib. Coadministration may increase the exposure of verapamil. Adagrasib is a strong inhibitor of CYP3A; verapamil is a substrate of CYP3A.
Vilazodone: (Major) Do not exceed a vilazodone dose of 20 mg once daily if coadministration with adagrasib is necessary; the original dose of vilazodone can be resumed if adagrasib is discontinued. Vilazodone is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased vilazodone exposure by 50%.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with adagrasib is necessary. Vinblastine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Vincristine Liposomal: (Major) Avoid coadministration of vincristine with adagrasib due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Vincristine: (Major) Avoid coadministration of vincristine with adagrasib due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with adagrasib is necessary. Vinorelbine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor.
Voclosporin: (Contraindicated) Concomitant use of voclosporin and adagrasib is contraindicated; concomitant use may increase the exposure of voclosporin and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Concomitant use may also result in additive risk for QT/QTc prolongation and torsade de pointes (TdP). Voclosporin is a sensitive CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased voclosporin exposure by approximately 19-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of clarithromycin with adagrasib due to the potential for increased exposure to adagrasib and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If coadministration is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation) and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use before adagrasib steady state is achieved may increase adagrasib exposure. Adagrasib is a CYP3A substrate, clarithromycin is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Vorapaxar: (Major) Avoid coadministration of vorapaxar with adagrasib due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
Voriconazole: (Contraindicated) Avoid concomitant use of adagrasib and voriconazole. Concomitant use may increase concentrations of both medications and result in additive risk for QT/QTc prolongation and torsade de pointes (TdP). The use of voriconazole with a CYP3A substrate that causes QT prolongation, such as adagrasib, is contraindicated per the manufacturer of voriconazole. If use is necessary, wait for adagrasib levels to reach steady state (approximately 8 days after initiation), monitor for voriconazole -related adverse effects, and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Concomitant use before adagrasib steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and strong CYP3A inhibitor, voriconazole is a CYP3A substrate and strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Vorinostat: (Major) Concomitant use of adagrasib and vorinostat increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with adagrasib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Warfarin is a CYP3A and CYP2C9 substrate and adagrasib is a strong CYP3A and moderate CYP2C9 inhibitor. Concomitant use of adagrasib 600 mg twice daily is predicted to increase warfarin overall exposure by 2.9-fold.
Zaleplon: (Moderate) Monitor for an increase in zaleplon-related adverse reactions, including excessive sedation and confusion, if coadministered with adagrasib. Routine dosage adjustments of zaleplon are not required. Zaleplon is partially metabolized by CYP3A. Adagrasib is a strong CYP3A inhibitor. Coadministration with a single dose of another strong CYP3A inhibitor increased the AUC of zaleplon by 20%.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with adagrasib. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Interrupt zanubrutinib therapy as recommended for adverse reactions. After discontinuation of adagrasib, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. The AUC of zanubrutinib was increased by 278% when coadministered with another strong CYP3A inhibitor.
Ziprasidone: (Major) Avoid concomitant use of adagrasib and ziprasidone due to the potential for increased ziprasidone exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for ziprasidone-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Ziprasidone is a CYP3A substrate, adagrasib is a strong CYP3A inhibitor, and both medications have been associated with QT interval prolongation. Coadministration with another strong CYP3A inhibitor increased the AUC of ziprasidone by approximately 35% to 40%.
Zolpidem: (Moderate) Consider decreasing the dose of zolpidem if coadministration with adagrasib is necessary. Concurrent use may increase zolpidem exposure. Zolpidem is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Coadministration with other strong CYP3A inhibitors increased the AUC of zolpidem by 34% to 70%.
Zuranolone: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with adagrasib is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Adagrasib is an irreversible KRAS G12C inhibitor. It covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive state; this prevents downstream signaling without affecting the wild-type KRAS protein. In KRAS G12C-mutated tumor xenograft models, adagrasib inhibited tumor cell growth and viability in cells harboring KRAS G12C mutations with minimal off-target activity.
Adagrasib is administered orally. It is approximately 98% protein bound in vitro. The apparent volume of distribution is 942 liters (coefficient of variation [CV], 57%). The terminal elimination half-life of adagrasib is 23 hours (CV, 16%) and the apparent oral clearance (CL/F) is 37 liters/hour (CV, 54%) in patients. Approximately 75% of a single radiolabeled dose of adagrasib was recovered in the feces (14% as unchanged drug) and 4.5% in the urine (2% as unchanged drug).
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2C8, CYP1A2, CYP2B6, CYP2C9, CYP2D6, BCRP, MATE-1/MATE-2K
Following single-dose administration, adagrasib is primarily metabolized by CYP3A4. At steady-state, adagrasib inhibits its own metabolism via CYP3A4; at steady state, adagrasib is metabolized by CYP2C8, CYP1A2, CYP2B6, CYP2C9, and CYP2D6. In vitro, adagrasib may be a substrate of BCRP and may inhibit CYP2B6 and MATE1/MATE2K.
-Route-Specific Pharmacokinetics
Oral Route
The AUC and Cmax of adagrasib increase in a dose proportional manner over a dose range of 400 mg to 600 mg (0.67 to 1 times the approved recommended dose). The median time to maximum concentration (Tmax) is approximately 6 hours. When administered at the recommended dose, steady-state was reached within 8 days; accumulation at steady-state is approximately 6-fold. A high-fat, high-calorie meal (900 to 1,000 calories; 50% fat) did not have a clinically significant effect on the pharmacokinetics of adagrasib.
-Special Populations
Hepatic Impairment
Mild to severe hepatic impairment (Child-Pugh A, B, or C) did not have a clinically significant effect on the pharmacokinetics of adagrasib.
Renal Impairment
Mild to severe renal impairment (CrCl 15 to 89 mL/min) did not have a clinically significant effect on the pharmacokinetics of adagrasib.
Geriatric
Age (19 to 89 years) did not have a clinically significant effect on the pharmacokinetics of adagrasib.
Gender Differences
Sex did not have a clinically significant effect on the pharmacokinetics of adagrasib.
Ethnic Differences
Race (White, Black, or Asian) did not have a clinically significant effect on the pharmacokinetics of adagrasib.
Obesity
Body weight (36 to 139 kg) did not have a clinically significant effect on the pharmacokinetics of adagrasib.
Other
Performance status (ECOG PS 0 or 1) and tumor burden did not have a clinically significant effect on the pharmacokinetics of adagrasib.