Sotorasib is an oral KRAS G12C inhibitor. KRAS mutations are often associated with resistance to targeted therapies and poor outcomes. Since the discovery of KRAS in 1982, mutations have been considered to be untreatable due to the lack of accessible binding pockets as well as toxicities associated with other therapies. Sotorasib is the first FDA-approved drug targeting KRAS, and is indicated for the treatment of KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) in patients who have received at least one prior systemic treatment. Sotorasib is approved for use in patients only with the KRAS G12C mutation present in either the tumor or plasma specimen. Hepatotoxicity may occur during treatment; monitor liver function tests at baseline and throughout treatment.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Take with or without food.
-If a dose is missed by more than 6 hours, take the next dose as prescribed the following day. Do not take 2 doses at the same time to make up for the missed dose.
-If vomiting occurs after taking sotorasib, do not take an additional dose. Take the next dose as prescribed the following day.
Oral Solid Formulations
-Swallow tablets whole. Do not chew, crush, or split tablets.
Extemporaneous Compounding-Oral
For oral administration in patients who have difficulty swallowing solids:
-Disperse tablets in 4 ounces (approximately 120 mL) of non-carbonated, room temperature water; do not mix with other liquids.
-Stir or swirl the cup for approximately 3 minutes, until tablets are dispersed into small pieces; they will not completely dissolve. Do not crush the tablets. The mixture will be pale to bright yellow.
-Drink immediately or within 2 hours. Do not chew pieces of the tablet. If the mixture is not consumed immediately, stir the mixture again to ensure that tablets are dispersed.
-Rinse the container with an additional 4 ounces (120 mL) of water and drink.
Hepatotoxicity occurred in 1.7% (grade 3, 1.4%) of patients with non-small cell lung cancer (NSCLC) and other solid tumors with KRAS G12C mutations in a multicenter, single-arm trial (n = 357); however, hepatotoxicity was reported in 25% (grade 3 or 4, 12%) of the subset of patients with locally advanced or metastatic NSCLC (n = 204) in this trial. The term hepatotoxicity included increased AST, increased ALT, hyperbilirubinemia, drug-induced liver injury, and hepatitis. Monitor liver function tests (AST, ALT, and total bilirubin) at baseline, every 3 weeks for the first 3 months of treatment, and then once monthly or as clinically indicated; more frequent testing is indicated in patients who develop transaminitis or hyperbilirubinemia. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary based on the severity of hepatotoxicity. Elevated hepatic enzymes (ALT and AST) occurred in 18% (grade 3 or 4, 6.6%) of patients in the total population and in 38% to 39% (grade 3 or 4, 9% to 11%) of those in the NSCLC subpopulation; increased alkaline phosphatase was reported in 33% (grade 3 or 4, 2.5%) of the NSCLC subpopulation. The median time to first onset of transaminitis was 9 weeks.
Interstitial lung disease (ILD)/pneumonitis occurred in 0.8% of patients with non-small cell lung cancer (NSCLC) and other solid tumors with KRAS G12C mutations treated with sotorasib in a multicenter, single-arm trial (n = 357); all cases were grade 3 or 4 at onset, and 1 case was fatal. The median time to onset was 2 weeks. Monitor patients for new or worsening pulmonary symptoms (e.g., cough, dyspnea, fever). Immediately withhold treatment in patients with suspected ILD/pneumonitis; permanently discontinue sotorasib if no other potential causes of ILD/pneumonitis are identified. Cough occurred in 20% (grade 3 or 4, 1.5%) and dyspnea in 16% (grade 3 or 4, 2.9%) of patients in the NSCLC subpopulation of this trial.
Diarrhea (42%; grade 3 or 4, 5%), nausea (26%; grade 3 or 4, 1%), vomiting (17%; grade 3 or 4, 1.5%), constipation (16%; grade 3 or 4, 0.5%), and abdominal pain (15%; grade 3 or 4, 1%) were reported in a subset of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (n = 204) in a multicenter, single-arm trial. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for grade 3 or 4 diarrhea despite appropriate antidiarrheal or antiemetic therapy.
Anorexia was reported in 13% (grade 3 or 4, 1%) of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (n = 204) in a multicenter, single-arm trial.
Musculoskeletal pain (35%; grade 3 or 4, 8%) and arthralgia (12%; grade 3 or 4, 1%) were reported in a subset of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (n = 204) in a multicenter, single-arm trial. The term "musculoskeletal pain" included back pain, bone pain, noncardiac chest pain, musculoskeletal discomfort, myalgia, neck pain, and extremity pain.
Infection, and specifically pneumonia, occurred in 12% (grade 3 or 4, 7%) of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (n = 204) in a multicenter, single-arm trial.
Fatigue (including asthenia) was reported in 26% (grade 3 or 4, 2%) of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (n = 204) in a multicenter, single-arm trial.
Edema occurred in 15% of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (n = 204) in a multicenter, single-arm trial, including generalized edema, peripheral edema, periorbital edema, and testicular edema.
Rash occurred in 12% of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (n = 204) in a multicenter, single-arm trial, including dermatitis, acneiform rash, maculopapular rash, and pustular rash.
Decreases from baseline in lymphocytes (lymphopenia) (48%; grade 3 or 4, 2%) and hemoglobin (anemia) (43%; grade 3 or 4, 0.5%) occurred in patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (n = 204) in a multicenter, single-arm trial, including dermatitis, acneiform rash, maculopapular rash, and pustular rash.
Prolonged bleeding time (increased activated partial thromboplastin time) occurred in 23% (grade 3 or 4, 1.5%) of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (n = 204) in a multicenter, single-arm trial.
Increased urine protein from baseline (proteinuria) occurred in 29% (grade 3 or 4, 3.9%) of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (n = 204) in a multicenter, single-arm trial.
Decreased albumin concentrations from baseline (hypoalbuminemia) occurred in 22% (grade 3 or 4, 0.5%) of patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (n = 204) in a multicenter, single-arm trial.
Decreases from baseline in sodium (hyponatremia) (28%; grade 3 or 4, 1%) and calcium (hypocalcemia) (35%) occurred in patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (n = 204) in a multicenter, single-arm trial.
Monitor patients with severe baseline hepatic disease (Child-Pugh C) more frequently for adverse reactions. The safety of sotorasib therapy in patients with severe hepatic impairment is unknown, but these patients may be at increased risk for adverse reactions including hepatotoxicity which was reported in patients with non-small cell lung cancer and other solid tumors with KRAS G12C mutations in a multicenter, single-arm trial. In all patients, monitor liver function tests (AST, ALT, and total bilirubin) at baseline, every 3 weeks for the first 3 months of treatment, and then once monthly or as clinically indicated; more frequent testing is indicated in patients who develop transaminitis or hyperbilirubinemia. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary based on the severity of hepatotoxicity. The median time to first onset of transaminitis was 9 weeks after initiation of therapy.
Use sotorasib with caution in patients with a history of chronic lung disease (CLD); interstitial lung disease (ILD)/pneumonitis has been reported in patients treated with sotorasib. The median time to first onset was 2 weeks from initiation of therapy. Monitor patients for new or worsening pulmonary symptoms (e.g., cough, dyspnea, fever). Immediately withhold treatment in patients with suspected ILD/pneumonitis; permanently discontinue sotorasib if no other potential causes of ILD/pneumonitis are identified.
There are no adequately controlled studies in of sotorasib use during pregnancy. However, in rat embryofetal development studies, sotorasib did not cause adverse developmental effects or embryolethality at exposures up to 4.6 times the human exposure at the 960 mg clinical dose when administered during organogenesis. In a rabbit embryofetal development study, administration of sotorasib during organogenesis resulted in lower fetal body weights and a reduction in the number of ossified metacarpals at exposures approximately 2.6 times the human exposure based on AUC at the recommended clinical dose; sotorasib did not cause adverse developmental effects or affect embryofetal survival at these doses.
Due to the potential for serious adverse reactions in nursing infants from sotorasib, advise women to discontinue breast-feeding during treatment and for 1 week after the final dose. It is not known whether sotorasib is present in human milk.
For the treatment of non-small cell lung cancer (NSCLC):
NOTE: The FDA has designated sotorasib as an orphan drug for the treatment of KRAS p.G12C-positive NSCLC.
-for the treatment of KRAS G12C-mutated locally advanced or metastatic NSCLC in patients who have received at least one prior systemic therapy:
NOTE: Patients should be selected based on the presence of a KRAS G12C mutation in tumor or plasma specimens; if a mutation is not detected in plasma, test tumor tissue. Information on FDA-approved tests for the determination of KRAS G12C mutations is available at www.fda.gov/CompanionDiagnostics.
Oral dosage:
Adults: 960 mg PO once 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 subset of patients enrolled in a multicenter, single-arm clinical trial (CodeBreaK 100), treatment with sotorasib resulted in an objective response rate of 36% (complete response, 2%) for a median duration of 10 months in patients with KRAS G12C-mutated locally advanced or metastatic NSCLC and disease progression after receiving an immune checkpoint inhibitor and/or platinum-based chemotherapy (n = 124); 58% of patients had a duration of response of at least 6 months.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
-First dose reduction: 480 mg PO once daily.
-Second dose reduction: 240 mg PO once daily. Discontinue sotorasib if patients are unable to tolerate a minimum dose of 240 mg PO once daily.
Diarrhea, Nausea, or Vomiting
-Grade 3 or 4 despite appropriate supportive care (including antidiarrheal or antiemetic therapy): Hold sotorasib therapy. Upon recovery to grade 1 or less (or baseline), resume sotorasib therapy at the next lower dose level. Discontinue therapy in patients unable to tolerate a dose of 240 mg once daily.
Interstitial Lung Disease (ILD)/Pneumonitis
-Any grade: Hold sotorasib if ILD/pneumonitis is suspected. Permanently discontinue therapy if ILD/pneumonitis is confirmed.
Other Adverse Reactions
-Grade 3 or 4: Hold sotorasib therapy. Upon recovery to grade 1 or less (or baseline), resume sotorasib therapy at the next lower dose level. Discontinue therapy in patients unable to tolerate a dose of 240 mg once daily.
Maximum Dosage Limits:
-Adults
960 mg PO once daily.
-Geriatric
960 mg PO once daily.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment
-Mild to moderate hepatic impairment (Child-Pugh A or B): No dosage adjustment is recommended.
-Severe hepatic impairment (Child-Pugh C): The safety of sotorasib is unknown; monitor more frequently for adverse reactions including hepatotoxicity.
Treatment-Related Hepatotoxicity
-Symptomatic grade 2 AST or ALT, or any grade 3 to 4 AST or ALT: Hold sotorasib therapy. Upon recovery to grade 1 or less (or baseline), resume sotorasib therapy at the next lower dose level. Discontinue therapy in patients unable to tolerate a dose of 240 mg once daily.
-AST or ALT greater than 3 times the upper limit of normal (ULN) with total bilirubin greater than 2 times ULN in the absence of alternative causes: Permanently discontinue sotorasib therapy.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. The effect of severe renal impairment (CrCl less than 30 mL/min/1.73 m2) on the pharmacokinetics of sotorasib has not been studied.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for decreased efficacy or increased toxicity of dolutegravir if coadministered with sotorasib. Concurrent use may alter the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4, BCRP, and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and a BCRP and P-gp inhibitor.
Abemaciclib: (Major) Avoid coadministration of sotorasib with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Abemaciclib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with other moderate CYP3A4 inducers is predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 29% to 53%.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal if coadministration with sotorasib is necessary; consider increasing the dose of dihydrocodeine as needed. If sotorasib is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs of respiratory depression and sedation. Sotorasib is a moderate inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. Concomitant use of dihydrocodeine with sotorasib can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with sotorasib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If sotorasib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sotorasib is a moderate CYP3A4 inducer. Concomitant use with sotorasib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Acetaminophen; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with sotorasib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If sotorasib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with sotorasib is necessary; consider increasing the dose of oxycodone as needed. If sotorasib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Afatinib: (Moderate) If the concomitant use of sotorasib 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 sotorasib. 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 sotorasib 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 and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
Alfentanil: (Moderate) Consider an increased dose of alfentanil and monitor for evidence of opioid withdrawal if coadministration with sotorasib is necessary. If sotorasib is discontinued, consider reducing the alfentanil dosage and monitor for evidence of respiratory depression. Coadministration of a moderate CYP3A4 inducer like sotorasib with alfentanil, a CYP3A4 substrate, may decrease exposure to alfentanil resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to alfentanil. Alfentanil plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Alpelisib: (Major) Avoid coadministration of alpelisib with sotorasib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and sotorasib is a BCRP inhibitor.
Aluminum Hydroxide: (Moderate) Avoid coadministration of sotorasib and gastric-reducing agents, such as antacids. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If coadministration with antacids is necessary, administer sotorasib 4 hours before or 10 hours after an antacid.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Avoid coadministration of sotorasib and gastric-reducing agents, such as antacids. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If coadministration with antacids is necessary, administer sotorasib 4 hours before or 10 hours after an antacid.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Avoid coadministration of sotorasib and gastric-reducing agents, such as antacids. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If coadministration with antacids is necessary, administer sotorasib 4 hours before or 10 hours after an antacid.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Avoid coadministration of sotorasib and gastric-reducing agents, such as antacids. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If coadministration with antacids is necessary, administer sotorasib 4 hours before or 10 hours after an antacid.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Avoid coadministration of sotorasib and gastric-reducing agents, such as antacids. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If coadministration with antacids is necessary, administer sotorasib 4 hours before or 10 hours after an antacid.
Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with sotorasib is necessary. Amlodipine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Atorvastatin: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with sotorasib is necessary. Amlodipine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine. (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sotorasib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; sotorasib is a P-gp and BCRP inhibitor.
Amlodipine; Benazepril: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with sotorasib is necessary. Amlodipine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Celecoxib: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with sotorasib is necessary. Amlodipine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Olmesartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with sotorasib is necessary. Amlodipine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Valsartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with sotorasib is necessary. Amlodipine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with sotorasib is necessary. Amlodipine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with a PPI decreased sotorasib exposure by 57% under fed conditions and 42% under fasted conditions. (Major) Consider alternatives to clarithromycin if treatment with sotorasib is necessary as concurrent use may decrease efficacy of clarithromycin. Clarithromycin is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A4 inducer.
Antacids: (Moderate) Avoid coadministration of sotorasib and gastric-reducing agents, such as antacids. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If coadministration with antacids is necessary, administer sotorasib 4 hours before or 10 hours after an antacid.
Apalutamide: (Major) Avoid concurrent use of sotorasib and apalutamide. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with sotorasib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If sotorasib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sotorasib is a moderate CYP3A4 inducer. Concomitant use with sotorasib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Aspirin, ASA; Omeprazole: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with a PPI decreased sotorasib exposure by 57% under fed conditions and 42% under fasted conditions.
Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with sotorasib is necessary; consider increasing the dose of oxycodone as needed. If sotorasib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Atazanavir: (Moderate) Monitor for decreased efficacy of atazanavir if coadministered with sotorasib. Concurrent use may decrease the plasma concentrations of atazanavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Atazanavir is a CYP3A substrate and sotorasib is a moderate CYP3A4 inducer.
Atazanavir; Cobicistat: (Moderate) Coadministration of cobicistat with sotorasib may result in decreased plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Moderate) Monitor for decreased efficacy of atazanavir if coadministered with sotorasib. Concurrent use may decrease the plasma concentrations of atazanavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Atazanavir is a CYP3A substrate and sotorasib is a moderate CYP3A4 inducer.
Atogepant: (Major) Avoid use of atogepant and sotorasib when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine if coadministered with sotorasib. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and sotorasib is a moderate CYP3A inducer.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sotorasib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; sotorasib is a P-gp and BCRP inhibitor.
Avacopan: (Major) Avoid concomitant use of avacopan and sotorasib due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and sotorasib is a moderate CYP3A inducer.
Avanafil: (Major) Coadministration of avanafil with sotorasib is not recommended due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil was not evaluated, plasma concentrations may decrease.
Avapritinib: (Major) Avoid coadministration of avapritinib with sotorasib due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer is predicted to decrease the AUC and Cmax of avapritinib by 62% and 55%, respectively.
Axitinib: (Major) Avoid coadministration of axitinib with sotorasib if possible due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and sotorasib is a moderate CYP3A4 inducer.
Bedaquiline: (Major) Avoid coadministration of sotorasib with bedaquiline due to decreased plasma exposure to bedaquiline. Bedaquiline is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased bedaquiline exposure by approximately 20%. The AUC and Cmax of the primary metabolite of bedaquiline (M2) were increased by 70% and 80%, respectively.
Benzhydrocodone; Acetaminophen: (Moderate) Monitor for reduced efficacy of benzhydrocodone and signs of opioid withdrawal if coadministration with sotorasib is necessary; consider increasing the dose of benzhydrocodone as needed. If sotorasib is discontinued, consider a dose reduction of benzhydrocodone and frequently monitor for signs of respiratory depression and sedation. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving sotorasib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving sotorasib. 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; sotorasib 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 sotorasib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate. Sotorasib is a P-gp and BCRP inhibitor.
Brigatinib: (Major) Avoid coadministration of brigatinib with sotorasib due to decreased plasma exposure to brigatinib which may result in decreased efficacy. If concomitant use is unavoidable, after 7 days of concomitant treatment with sotorasib, increase the dose of brigatinib as tolerated in 30 mg increments to a maximum of twice the original brigatinib dose. After discontinuation of sotorasib, resume the brigatinib dose that was tolerated prior to initiation of sotorasib. Brigatinib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease the AUC of brigatinib by approximately 50%.
Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and sotorasib are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; sotorasib is a moderate inducer of CYP3A4.
Buprenorphine: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with sotorasib is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If sotorasib is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and sotorasib is a CYP3A4 inducer.
Buprenorphine; Naloxone: (Moderate) Monitor for decreased efficacy of buprenorphine, and potentially the onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine, if coadministration with sotorasib is necessary; consider increasing the dose of buprenorphine until stable drug effects are achieved. If sotorasib is discontinued, consider a buprenorphine dose reduction and monitor for signs of respiratory depression. Buprenorphine is a CYP3A4 substrate and sotorasib is a CYP3A4 inducer.
Buspirone: (Moderate) Monitor for decreased efficacy of buspirone if sotorasib is added to a patient on a stable dosage of buspirone; a dose increase of buspirone may be needed to maintain anxiolytic activity. Buspirone is a sensitive CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with sotorasib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If sotorasib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sotorasib is a moderate CYP3A4 inducer. Concomitant use with sotorasib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with sotorasib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If sotorasib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sotorasib is a moderate CYP3A4 inducer. Concomitant use with sotorasib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Cabotegravir; Rilpivirine: (Moderate) Coadministration of rilpivirine with sotorasib may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Calcium Carbonate: (Moderate) Avoid coadministration of sotorasib and gastric-reducing agents, such as antacids including calcium carbonate. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If coadministration with calcium carbonate is necessary, administer sotorasib 4 hours before or 10 hours after calcium carbonate.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as H2-receptor antagonists. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with an H2-receptor antagonist decreased sotorasib exposure by 38% under fed conditions. (Moderate) Avoid coadministration of sotorasib and gastric-reducing agents, such as antacids including calcium carbonate. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If coadministration with calcium carbonate is necessary, administer sotorasib 4 hours before or 10 hours after calcium carbonate.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Avoid coadministration of sotorasib and gastric-reducing agents, such as antacids including calcium carbonate. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If coadministration with calcium carbonate is necessary, administer sotorasib 4 hours before or 10 hours after calcium carbonate.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Avoid coadministration of sotorasib and gastric-reducing agents, such as antacids including calcium carbonate. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If coadministration with calcium carbonate is necessary, administer sotorasib 4 hours before or 10 hours after calcium carbonate.
Calcium Carbonate; Simethicone: (Moderate) Avoid coadministration of sotorasib and gastric-reducing agents, such as antacids including calcium carbonate. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If coadministration with calcium carbonate is necessary, administer sotorasib 4 hours before or 10 hours after calcium carbonate.
Calcium; Vitamin D: (Moderate) Avoid coadministration of sotorasib and gastric-reducing agents, such as antacids including calcium carbonate. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If coadministration with calcium carbonate is necessary, administer sotorasib 4 hours before or 10 hours after calcium carbonate.
Capivasertib: (Major) Avoid coadministration of capivasertib with sotorasib due to decreased capivasertib exposure and risk of decreased efficacy. Capivasertib is a CYP3A substrate; sotorasib is a moderate CYP3A inducer. Coadministration of another moderate CYP3A inducer is predicted to decrease the capivasertib overall exposure by 60%.
Capmatinib: (Major) Avoid coadministration of capmatinib and sotorasib due to the risk of decreased capmatinib exposure which may reduce its efficacy. Capmatinib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased capmatinib exposure by 44%.
Carbamazepine: (Major) Avoid concurrent use of sotorasib and carbamazepine. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Concomitant use may also decrease carbamazepine concentrations. Sotorasib is a CYP3A4 substrate and moderate CYP3A4 inducer; carbamazepine is a CYP3A4 substrate and strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
Cariprazine: (Major) Coadministration of cariprazine with sotorasib is not recommended as the net effect of CYP3A4 induction on cariprazine and its metabolites is unclear. Cariprazine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration of cariprazine with CYP3A4 inducers has not been evaluated.
Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with sotorasib is necessary; consider increasing the dose of tramadol as needed. If sotorasib is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Chlorpheniramine; Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with sotorasib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If sotorasib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sotorasib is a moderate CYP3A4 inducer. Concomitant use with sotorasib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Chlorpheniramine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with sotorasib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If sotorasib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cimetidine: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as H2-receptor antagonists. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with an H2-receptor antagonist decreased sotorasib exposure by 38% under fed conditions.
Clarithromycin: (Major) Consider alternatives to clarithromycin if treatment with sotorasib is necessary as concurrent use may decrease efficacy of clarithromycin. Clarithromycin is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A4 inducer.
Clozapine: (Moderate) Monitor for loss of clozapine effectiveness if coadministered with sotorasib. Consideration should be given to increasing the clozapine dose if necessary. When sotorasib is discontinued, reduce the clozapine dose based on clinical response. Sotorasib is a moderate inducer of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine.
Cobicistat: (Moderate) Coadministration of cobicistat with sotorasib may result in decreased plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Cobimetinib: (Major) Avoid coadministration of cobimetinib with sotorasib as concurrent use may alter cobimetinib exposure, which may lead to decreased efficacy or increased toxicity. Cobimetinib is a CYP3A4 and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor.
Codeine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with sotorasib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If sotorasib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sotorasib is a moderate CYP3A4 inducer. Concomitant use with sotorasib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Guaifenesin: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with sotorasib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If sotorasib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sotorasib is a moderate CYP3A4 inducer. Concomitant use with sotorasib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with sotorasib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If sotorasib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sotorasib is a moderate CYP3A4 inducer. Concomitant use with sotorasib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with sotorasib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If sotorasib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sotorasib is a moderate CYP3A4 inducer. Concomitant use with sotorasib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Codeine; Promethazine: (Moderate) Monitor for reduced efficacy of codeine and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with sotorasib is necessary; consider increasing the dose of codeine as needed. It is recommended to avoid this combination when codeine is being used for cough. If sotorasib is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sotorasib is a moderate CYP3A4 inducer. Concomitant use with sotorasib can increase norcodeine levels via increased CYP3A4 metabolism, resulting in decreased metabolism via CYP2D6 resulting in lower morphine levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Colchicine: (Major) Avoid concomitant use of colchicine and sotorasib 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 P-gp substrate and sotorasib is a P-gp inhibitor.
Conjugated Estrogens: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Conjugated Estrogens; Bazedoxifene: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Conjugated Estrogens; Medroxyprogesterone: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Cyclosporine: (Moderate) Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with sotorasib is necessary. Concurrent use may alter cyclosporine exposure resulting in decreased efficacy or increased toxicity. Cyclosporine is a CYP3A4 and P-gp substrate and has a narrow therapeutic index; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor.
Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with sotorasib is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/min. Avoid coadministration in patients with CrCl less than 50 mL/min 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/min 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-glycoprotein substrate and sotorasib is a P-gp inhibitor.
Dapsone: (Moderate) Closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia if coadministration with sotorasib is necessary. Dapsone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration may decrease plasma concentrations of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis).
Daridorexant: (Major) Avoid concomitant use of daridorexant and sotorasib. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Concomitant use of another moderate CYP3A inducer decreased daridorexant overall exposure by over 50%.
Darunavir: (Moderate) Coadministration of darunavir with sotorasib may result in decreased plasma concentrations of darunavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Darunavir; Cobicistat: (Moderate) Coadministration of cobicistat with sotorasib may result in decreased plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Moderate) Coadministration of darunavir with sotorasib may result in decreased plasma concentrations of darunavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of cobicistat with sotorasib may result in decreased plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Moderate) Coadministration of darunavir with sotorasib may result in decreased plasma concentrations of darunavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Moderate) Coadministration of tenofovir alafenamide with sotorasib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate. Sotorasib is a P-gp and BCRP inhibitor.
Deflazacort: (Major) Avoid concomitant use of deflazacort and sotorasib. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; sotorasib is a moderate inducer of CYP3A4. Administration of deflazacort with multiple doses of another strong CYP3A4 inducer resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
Delavirdine: (Moderate) Coadministration of delavirdine with sotorasib may result in decreases in the plasma concentrations of delavirdine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Delavirdine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased delavirdine exposure by 82%.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Desogestrel; Ethinyl Estradiol: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Dexlansoprazole: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with a PPI decreased sotorasib exposure by 57% under fed conditions and 42% under fasted conditions.
Diazepam: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with sotorasib is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A4 substrate and sotorasib is a CYP3A4 inducer.
Dienogest; Estradiol valerate: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Digoxin: (Moderate) Increase monitoring of serum digoxin concentrations and watch for potential signs and symptoms of clinical toxicity when starting, adjusting, or discontinuing sotorasib. Concurrent use may increase digoxin exposure. Digoxin is a P-gp substrate with a narrow therapeutic index and sotorasib is a P-gp inhibitor.
Diltiazem: (Moderate) Avoid coadministration of diltiazem and sotorasib if possible due to decreased plasma concentrations of diltiazem; if unavoidable, monitor blood pressure and heart rate and adjust the diltiazem dose based on clinical response. Diltiazem is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased diltiazem exposure by 69% and decreased exposure to desacetyldiltiazem by 75%.
Dolutegravir: (Moderate) Monitor for decreased efficacy or increased toxicity of dolutegravir if coadministered with sotorasib. Concurrent use may alter the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4, BCRP, and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and a BCRP and P-gp inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for decreased efficacy or increased toxicity of dolutegravir if coadministered with sotorasib. Concurrent use may alter the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4, BCRP, and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and a BCRP and P-gp inhibitor.
Dolutegravir; Rilpivirine: (Moderate) Coadministration of rilpivirine with sotorasib may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Moderate) Monitor for decreased efficacy or increased toxicity of dolutegravir if coadministered with sotorasib. Concurrent use may alter the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4, BCRP, and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and a BCRP and P-gp inhibitor.
Doravirine: (Moderate) Concurrent administration of doravirine and sotorasib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with sotorasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and sotorasib is a P-gp and BCRP inhibitor. (Moderate) Concurrent administration of doravirine and sotorasib may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer.
Doxorubicin Liposomal: (Major) Avoid coadministration of doxorubicin with sotorasib due to altered doxorubicin plasma concentrations, which may lead to increased toxicity or decreased efficacy. Doxorubicin is a CYP3A4 and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
Doxorubicin: (Major) Avoid coadministration of doxorubicin with sotorasib due to altered doxorubicin plasma concentrations, which may lead to increased toxicity or decreased efficacy. Doxorubicin is a CYP3A4 and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy.
Dronabinol: (Moderate) Monitor for a decrease in dronabinol efficacy if coadministration with sotorasib is necessary. Coadministration may decrease the exposure of dronabinol. Dronabinol is a CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer.
Drospirenone: (Major) Women taking both drospirenone and sotorasib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. For patients on hormone replacement treatments (HRT) with drospirenone, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Drospirenone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Drospirenone; Estetrol: (Major) Women taking both drospirenone and sotorasib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. For patients on hormone replacement treatments (HRT) with drospirenone, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Drospirenone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Drospirenone; Estradiol: (Major) Women taking both drospirenone and sotorasib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. For patients on hormone replacement treatments (HRT) with drospirenone, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Drospirenone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Drospirenone; Ethinyl Estradiol: (Major) Women taking both drospirenone and sotorasib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. For patients on hormone replacement treatments (HRT) with drospirenone, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Drospirenone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Women taking both drospirenone and sotorasib should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. For patients on hormone replacement treatments (HRT) with drospirenone, monitor for altered clinical response, such as increased hot flashes, vaginal dryness, changes in withdrawal bleeding, or other signs of decreased hormonal efficacy. Drospirenone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Duvelisib: (Major) Avoid concomitant use of duvelisib with sotorasib. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib. If concomitant use is necessary, increase the dose of duvelisib on day 12 of coadministration from 25 mg PO twice daily to 40 mg PO twice daily; or from 15 mg PO twice daily to 25 mg PO twice daily. When sotorasib has been discontinued for at least 14 days, resume duvelisib at the dose taken prior to initiating treatment with sotorasib. Duvelisib is a CYP3A substrate; sotorasib is a moderate CYP3A inducer. Coadministration of duvelisib with another moderate CYP3A inducer for 12 days decreased duvelisib exposure by 35%.
Edoxaban: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of sotorasib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and sotorasib 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 sotorasib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of sotorasib. Increased concentrations of edoxaban may occur during concomitant use of sotorasib; monitor for increased adverse effects of edoxaban.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with sotorasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and sotorasib is a P-gp and BCRP inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with sotorasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and sotorasib is a P-gp and BCRP inhibitor.
Elacestrant: (Major) Avoid concurrent use of elacestrant and sotorasib due to the risk of decreased elacestrant exposure which may reduce its efficacy. Elacestrant is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced elacestrant overall exposure by 55% to 73%.
Elagolix; Estradiol; Norethindrone acetate: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Elbasvir; Grazoprevir: (Major) Coadministration of elbasvir with sotorasib is not recommended due to decreased exposure of elbasvir, resulting in decreased virologic response. Elbasvir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Major) Concomitant use of grazoprevir and sotorasib is not recommended due to decreased exposure of grazoprevir, resulting in decreased virologic response. Grazoprevir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of cobicistat with sotorasib may result in decreased plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Moderate) Coadministration of elvitegravir with sotorasib may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Elvitegravir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Moderate) Coadministration of tenofovir alafenamide with sotorasib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate. Sotorasib is a P-gp and BCRP inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of cobicistat with sotorasib may result in decreased plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Moderate) Coadministration of elvitegravir with sotorasib may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Elvitegravir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Moderate) Coadministration of tenofovir disoproxil fumarate with sotorasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and sotorasib is a P-gp and BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of rilpivirine with sotorasib may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Moderate) Coadministration of tenofovir alafenamide with sotorasib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate. Sotorasib is a P-gp and BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of rilpivirine with sotorasib may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Moderate) Coadministration of tenofovir disoproxil fumarate with sotorasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and sotorasib is a P-gp and BCRP inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with sotorasib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate. Sotorasib is a P-gp and BCRP inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with sotorasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and sotorasib is a P-gp and BCRP inhibitor.
Encorafenib: (Major) Avoid concurrent use of sotorasib and encorafenib. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the overall exposure of sotorasib by 51%.
Entrectinib: (Major) Avoid coadministration of entrectinib with sotorasib due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer. Coadministration of a moderate CYP3A4 inducer is predicted to reduce the entrectinib AUC by 56%.
Enzalutamide: (Major) Avoid concurrent use of sotorasib and enzalutamide. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
Erdafitinib: (Major) If coadministration of erdafitinib and sotorasib is necessary at the initiation of erdafitinib therapy, increase the dose of erdafitinib to 9 mg once daily. Erdafitinib is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced erdafitinib overall exposure by 45%.
Erlotinib: (Major) Avoid coadministration of erlotinib with sotorasib if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Esomeprazole: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with a PPI decreased sotorasib exposure by 57% under fed conditions and 42% under fasted conditions.
Esterified Estrogens: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Esterified Estrogens; Methyltestosterone: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estradiol: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estradiol; Levonorgestrel: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estradiol; Norethindrone: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estradiol; Norgestimate: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estradiol; Progesterone: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estrogens affected by CYP3A inducers: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estropipate: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Ethinyl Estradiol; Norelgestromin: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Ethinyl Estradiol; Norethindrone Acetate: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Ethinyl Estradiol; Norgestrel: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Etonogestrel; Ethinyl Estradiol: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Etravirine: (Moderate) Concurrent use of etravirine and sotorasib may decrease plasma concentrations of etravirine, leading to a reduction of antiretroviral efficacy and the potential development of antiretroviral drug resistance. Although specific recommendations are unavailable for use with sotorasib, coadministration with other moderate CYP3A4 inducers is not recommended. Etravirine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Concurrent use of another moderate CYP3A4 inducer decreased etravirine exposure by approximately 35%.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate if coadministration with sotorasib is necessary. Concurrent use may alter the exposure of everolimus, which may result in decreased efficacy or increased toxicity. The dose of everolimus may need to be adjusted. Everolimus is a sensitive CYP3A4 and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sotorasib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; sotorasib is a P-gp inhibitor.
Famotidine: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as H2-receptor antagonists. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with an H2-receptor antagonist decreased sotorasib exposure by 38% under fed conditions.
Fedratinib: (Major) Avoid coadministration of fedratinib with sotorasib as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer. Coadministration of fedratinib with another moderate CYP3A4 inducer decreased the overall exposure of fedratinib by 47%.
Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of sotorasib is necessary. If sotorasib is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like sotorasib with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
Finerenone: (Major) Avoid concurrent use of finerenone and sotorasib due to the risk for decreased finerenone exposure which may reduce its efficacy. Finerenone is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased overall exposure to finerenone by 80%.
Flibanserin: (Major) Avoid concomitant use of flibanserin and sotorasib due to the potential for decreased plasma concentrations of flibanserin. Flibanserin is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased flibanserin exposure by approximately 21%.
Fosamprenavir: (Moderate) Monitor for decreased fosamprenavir efficacy if coadministered with sotorasib. Concurrent use may decrease the plasma concentrations of fosamprenavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Fosamprenavir is a CYP3A substrate and sotorasib is a moderate CYP3A inducer.
Fosphenytoin: (Major) Avoid concurrent use of sotorasib and fosphenytoin. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
Fruquintinib: (Major) Avoid coadministration of fruquintinib with sotorasib if possible due to decreased fruquintinib exposure and risk of decreased efficacy. If concomitant use of fruquintinib and sotorasib is necessary, monitor for decreased efficacy. Fruquintinib is a CYP3A substrate; sotorasib is a strong CYP3A inducer. Coadministration of a moderate CYP3A inducer is predicted to decrease fruquintinib exposure by 32%.
Ganaxolone: (Major) Avoid concurrent use of ganaxolone and sotorasib due to the risk of decreased ganaxolone efficacy. If concomitant use is unavoidable, consider increasing ganaxolone dose without exceeding the maximum daily dose. Ganaxolone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and sotorasib as altered plasma concentrations of glecaprevir may occur resulting in the potential loss of efficacy of glecaprevir or increased toxicity. Glecaprevir is a CYP3A4, BCRP, and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and a BCRP and P-gp inhibitor. (Moderate) Monitor for an increase in pibrentasvir-related adverse effects if concomitant use of sotorasib is necessary. Concomitant use may increase pibrentasvir exposure. Pibrentasvir is a substrate of P-gp and BCRP. Sotorasib is a P-gp and BCRP inhibitor.
Guanfacine: (Major) A dose increase of extended-release (ER) guanfacine should be considered if coadministration with sotorasib is necessary. Consider doubling the recommended dose of guanfacine if therapy is added to a patient already taking sotorasib; increase the dose of guanfacine over one to two weeks if sotorasib therapy is added to a patient already taking guanfacine. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
H2-blockers: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as H2-receptor antagonists. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with an H2-receptor antagonist decreased sotorasib exposure by 38% under fed conditions.
Homatropine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with sotorasib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If sotorasib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with sotorasib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If sotorasib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
Hydrocodone; Ibuprofen: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal in patients who have developed physical dependence if coadministration with sotorasib is necessary; consider increasing the dose of hydrocodone as needed. It is recommended to avoid this combination when hydrocodone is being used for cough. If sotorasib is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs of respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Concomitant use can decrease hydrocodone levels.
Ibrexafungerp: (Major) Avoid concurrent administration of ibrexafungerp with sotorasib. Use of these drugs together is expected to significantly decrease ibrexafungerp exposure, which may reduce its efficacy. Ibrexafungerp is a CYP3A substrate and sotorasib is a moderate CYP3A inducer.
Ibuprofen; Famotidine: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as H2-receptor antagonists. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with an H2-receptor antagonist decreased sotorasib exposure by 38% under fed conditions.
Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with sotorasib is necessary; consider increasing the dose of oxycodone as needed. If sotorasib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with sotorasib is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4; sotorasib is a moderate CYP3A4 inducer. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
Indinavir: (Moderate) Coadministration of indinavir with sotorasib may result in decreased plasma concentrations of indinavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Although specific recommendations are unavailable for use with sotorasib, an increased indinavir dose is recommended (i.e., 1,000 mg PO every 8 hours) when coadministered with other moderate CYP3A4 inducers. Indinavir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased indinavir exposure by up to 46%.
Infigratinib: (Major) Avoid concurrent use of infigratinib and sotorasib. Coadministration may decrease infigratinib exposure resulting in decreased efficacy. Infigratinib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concurrent use of sotorasib and rifampin. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the AUC of sotorasib by 51%.
Isoniazid, INH; Rifampin: (Major) Avoid concurrent use of sotorasib and rifampin. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the AUC of sotorasib by 51%.
Isradipine: (Moderate) Monitor for decreased efficacy of isradipine if coadministration with sotorasib is necessary. Concomitant use may decrease isradipine exposure. Isradipine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with sotorasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and sotorasib is a P-gp and BCRP inhibitor.
Lansoprazole: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with a PPI decreased sotorasib exposure by 57% under fed conditions and 42% under fasted conditions.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with a PPI decreased sotorasib exposure by 57% under fed conditions and 42% under fasted conditions. (Major) Consider alternatives to clarithromycin if treatment with sotorasib is necessary as concurrent use may decrease efficacy of clarithromycin. Clarithromycin is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A4 inducer.
Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with sotorasib is necessary. Lapatinib is a P-gp substrate and sotorasib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
Larotrectinib: (Major) Avoid concurrent use of larotrectinib and sotorasib due to the risk of decreased larotrectinib exposure which may reduce its efficacy. If concomitant use is necessary, double the dose of larotrectinib and monitor response. If sotorasib is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of sotorasib. Larotrectinib is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Coadministration with a moderate CYP3A inducer is predicted to decrease larotrectinib exposure by 72%.
Lefamulin: (Major) Avoid coadministration of lefamulin with sotorasib unless the benefits outweigh the risks as concurrent use may alter lefamulin exposure, which may lead to increased toxicity or decreased efficacy. Lefamulin is a CYP3A4 and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor.
Lemborexant: (Major) Avoid coadministration of lemborexant and sotorasib as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer.
Lenacapavir: (Major) Avoid concurrent use of lenacapavir and sotorasib due to the risk of decreased lenacapavir exposure which may result in loss of therapeutic effect and development of resistance. Lenacapavir is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced lenacapavir overall exposure by 56%.
Leniolisib: (Major) Avoid concomitant use of leniolisib and sotorasib. Concomitant use may decrease leniolisib exposure which may reduce its efficacy. Leniolisib is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer reduced leniolisib overall exposure by 58%.
Levamlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with sotorasib is necessary. Amlodipine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Levonorgestrel; Ethinyl Estradiol: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and sotorasib is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with sotorasib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and sotorasib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with sotorasib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and sotorasib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Moderate) Monitor for decreased efficacy of lopinavir if concurrent sotorasib use is necessary. Concurrent use may decrease lopinavir exposure and increase the risk of virologic failure and drug resistance. Lopinavir is a CYP3A substrate and sotorasib is a moderate CYP3A4 inducer. (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with sotorasib. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and sotorasib is a moderate CYP3A4 inducer.
Lorlatinib: (Major) Avoid concomitant use of lorlatinib and sotorasib due to decreased plasma concentrations of lorlatinib, which may reduce its efficacy. If concomitant use is necessary, increase the dose of lorlatinib to 125 mg PO once daily. Lorlatinib is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Administration with another moderate CYP3A inducer decreased lorlatinib exposure by 23%.
Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sotorasib is necessary. Concomitant use may increase lovastatin exposure. Lovastatin is a substrate of P-gp; sotorasib is an inhibitor of P-gp.
Lumacaftor; Ivacaftor: (Major) Avoid concurrent use of sotorasib and lumacaftor; ivacaftor. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and combination lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
Lumacaftor; Ivacaftor: (Major) Avoid concurrent use of sotorasib and lumacaftor; ivacaftor. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and combination lumacaftor; ivacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
Lumateperone: (Major) Avoid coadministration of lumateperone and sotorasib as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer.
Lurasidone: (Moderate) If lurasidone is used with sotorasib, it may be necessary to increase the lurasidone dose after chronic treatment (7 days or more) with sotorasib. Concurrent use may lead to a decrease in efficacy of lurasidone. Sotorasib is a moderate CYP3A4 inducer; lurasidone is a CYP3A4 substrate.
Magnesium Hydroxide: (Moderate) Avoid coadministration of sotorasib and gastric-reducing agents, such as antacids. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If coadministration with antacids is necessary, administer sotorasib 4 hours before or 10 hours after an antacid.
Magnesium Salts: (Moderate) Avoid coadministration of sotorasib and gastric-reducing agents, such as antacids. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If coadministration with antacids is necessary, administer sotorasib 4 hours before or 10 hours after an antacid.
Maraviroc: (Major) Avoid concurrent use of sotorasib and maraviroc due to unpredictable effects. Coadministration may alter the exposure of maraviroc resulting in decreased efficacy or increased toxicity. Maraviroc is a CYP3A4 and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with sotorasib due to risk for reduced mavacamten efficacy. Concomitant use decreases mavacamten exposure. Mavacamten is a CYP3A substrate and sotorasib is a moderate CYP3A inducer.
Mefloquine: (Moderate) Monitor for an increase in mefloquine-related adverse effects or decrease in efficacy if concomitant use of sotorasib is necessary. Concomitant use may alter mefloquine exposure. Mefloquine is a CYP3A4 and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor.
Meperidine: (Moderate) Monitor for reduced efficacy of meperidine and signs of opioid withdrawal if coadministration with sotorasib is necessary. Consider increasing the dose of meperidine as needed. If sotorasib is discontinued, consider a dose reduction of meperidine and frequently monitor for signs of respiratory depression and sedation. Meperidine is a substrate of CYP3A4; sotorasib is a moderate CYP3A4 inducer. Concomitant use can decrease meperidine exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Methadone: (Moderate) Monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with sotorasib is necessary. Consider increasing the dose of methadone as needed. If sotorasib is discontinued, consider a dose reduction of methadone and frequently monitor for signs of respiratory depression and sedation. Methadone is a substrate of CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; sotorasib is a moderate CYP3A inducer. Concomitant use can decrease methadone exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Mitapivat: (Major) Avoid coadministration of mitapivat with sotorasib, if possible, due to decreased mitapivat efficacy. Coadministration decreases mitapivat concentrations. If concomitant use is necessary, up-titration of mitapivat may be required. Monitor hemoglobin and titrate the mitapivat dose based on response; do not exceed 100 mg PO twice daily. Mitapivat is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased mitapivat overall exposure by 55% to 60%.
Mitotane: (Major) Avoid concurrent use of sotorasib and mitotane. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and sotorasib. Coadministration may decrease mobocertinib exposure resulting in decreased efficacy. Mobocertinib is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Use of a moderate CYP3A inducer is predicted to decrease the overall exposure of mobocertinib and its active metabolites by 58%.
Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with sotorasib is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and sotorasib 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 sotorasib is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and sotorasib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with sotorasib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a P-gp substrate; sotorasib is a P-gp inhibitor.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with sotorasib is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and sotorasib. Concomitant use may alter sirolimus exposure resulting in decreased efficacy or increased risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and sotorasib is a moderate CYP3A inducer and P-gp inhibitor.
Naproxen; Esomeprazole: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with a PPI decreased sotorasib exposure by 57% under fed conditions and 42% under fasted conditions.
Nelfinavir: (Moderate) Monitor for decreased efficacy of nelfinavir if coadministered with sotorasib. Concurrent use may decrease the plasma concentrations of nelfinavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nelfinavir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Neratinib: (Major) Avoid concomitant use of sotorasib with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Simulations using physiologically based pharmacokinetic (PBPK) models suggest that a moderate CYP3A4 inducer may decrease neratinib exposure by 52%.
Nimodipine: (Moderate) Monitor for decreased efficacy of nimodipine if coadministration with sotorasib is necessary as concomitant use may decrease plasma concentrations of nimodipine. Nimodipine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Nirmatrelvir; Ritonavir: (Moderate) Monitor for a diminished response to nirmatrelvir if concomitant use of sotorasib is necessary. Concomitant use of nirmatrelvir and sotorasib may reduce the therapeutic effect of nirmatrelvir. Nirmatrelvir is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with sotorasib. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and sotorasib is a moderate CYP3A4 inducer.
Nirogacestat: (Major) Avoid concomitant use of nirogacestat and sotorasib. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer is predicted to reduce nirogacestat overall exposure by 67%.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with sotorasib as concurrent use may decrease nisoldipine exposure and efficacy. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and sotorasib is a CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
Nizatidine: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as H2-receptor antagonists. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with an H2-receptor antagonist decreased sotorasib exposure by 38% under fed conditions.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Norethindrone; Ethinyl Estradiol: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Norgestimate; Ethinyl Estradiol: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Olaparib: (Major) Avoid coadministration of olaparib with sotorasib due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with a moderate CYP3A4 inducer is predicted to decrease the olaparib Cmax by 31% and the AUC by 60%.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with sotorasib is necessary. Amlodipine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Olutasidenib: (Major) Avoid concurrent use of olutasidenib and sotorasib due to the risk of decreased olutasidenib exposure which may reduce its efficacy. Olutasidenib is a CYP3A substrate and sotorasib is a moderate CYP3A inducer.
Omaveloxolone: (Major) Avoid concurrent use of omaveloxolone and sotorasib. Concurrent use may decrease omaveloxolone exposure which may reduce its efficacy. Omaveloxolone is a CYP3A substrate and sotorasib is a moderate CYP3A inducer.
Omeprazole: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with a PPI decreased sotorasib exposure by 57% under fed conditions and 42% under fasted conditions.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with a PPI decreased sotorasib exposure by 57% under fed conditions and 42% under fasted conditions.
Omeprazole; Sodium Bicarbonate: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with a PPI decreased sotorasib exposure by 57% under fed conditions and 42% under fasted conditions.
Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with sotorasib is necessary; consider increasing the dose of oxycodone as needed. If sotorasib is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Paclitaxel: (Moderate) Monitor for decreased efficacy of paclitaxel if coadministration with sotorasib is necessary due to the risk of decreased plasma concentrations of paclitaxel. Paclitaxel is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Pacritinib: (Major) Avoid concurrent use of pacritinib with sotorasib due to the risk of decreased pacritinib exposure which may impair efficacy. Pacritinib is a CYP3A substrate and sotorasib is a moderate CYP3A inducer.
Palovarotene: (Major) Avoid concomitant use of palovarotene and sotorasib. Concurrent use may decrease palovarotene exposure which may reduce its efficacy. Palovarotene is a CYP3A substrate and sotorasib is a moderate CYP3A inducer.
Pantoprazole: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with a PPI decreased sotorasib exposure by 57% under fed conditions and 42% under fasted conditions.
Pazopanib: (Major) Avoid coadministration of pazopanib and sotorasib due to the potential for increased pazopanib exposure. Pazopanib is a P-gp and BCRP substrate; sotorasib is a P-gp and BCRP inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit P-gp or BCRP.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and sotorasib due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease pemigatinib exposure by more than 50%.
Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime if perampanel is added to sotorasib therapy; increase the dose as tolerated in 2 mg increments no more than weekly, based on clinical response. If sotorasib is added or withdrawn from perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Perindopril; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with sotorasib is necessary. Amlodipine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Phenobarbital: (Major) Avoid concurrent use of sotorasib and phenobarbital. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concurrent use of sotorasib and phenobarbital. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
Phenytoin: (Major) Avoid concurrent use of sotorasib and phenytoin. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
Pimavanserin: (Major) Avoid coadministration of pimavanserin with sotorasib as concurrent use may decrease pimavanserin exposure which may lead to decreased efficacy. Pimavanserin is a CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease the exposure of pimavanserin by approximately 70%.
Pirtobrutinib: (Major) Avoid concurrent use of pirtobrutinib and sotorasib due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. If concomitant use is necessary, an empiric pirtobrutinib dosage increase is required. If the current dosage is 200 mg once daily, increase the dose to 300 mg; if the current dosage is 50 mg or 100 mg once daily, increase the dose by 50 mg. Pirtobrutinib is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Pitavastatin: (Moderate) Monitor for an increase in pitavastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sotorasib is necessary. Concomitant use may increase pitavastatin exposure. Pitavastatin is a P-gp substrate; sotorasib is a P-gp inhibitor.
Posaconazole: (Moderate) Monitor for an increase in posaconazole-related adverse reactions if coadministration with sotorasib is necessary. Concomitant use may increase posaconazole exposure. Posaconazole is a P-gp substrate; sotorasib is a P-gp inhibitor.
Pralsetinib: (Major) Avoid concomitant use of sotorasib with pralsetinib due to the risk of altered pralsetinib exposure which may reduce its efficacy or increase the risk of adverse reactions. Pralsetinib is a CYP3A and P-gp substrate and sotorasib is a moderate CYP3A inducer and P-gp inhibitor. Coadministration with another moderate CYP3A inducer decreased the pralsetinib overall exposure by 45% and coadministration with another P-gp inhibitor increased the overall exposure of pralsetinib by 81%.
Praziquantel: (Major) Avoid concomitant use of praziquantel and sotorasib. Concurrent use may decrease praziquantel exposure which may reduce its efficacy. If concomitant use is necessary, monitor for reduced response to praziquantel. Praziquantel is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. When praziquantel was administered after 13 days of treatment with a moderate CYP3A inducer, the mean praziquantel AUC was 77% lower than when praziquantel was given alone.
Pretomanid: (Major) Avoid coadministration of pretomanid with sotorasib as concurrent use may decrease pretomanid exposure which may lead to decreased efficacy. Pretomanid is a CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer. Coadministration with another moderate CYP3A4 inducer decreased pretomanid exposure by 35%.
Primidone: (Major) Avoid concurrent use of sotorasib and primidone. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and sotorasib 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 P-gp substrate and sotorasib is a P-gp inhibitor.
Proton pump inhibitors: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with a PPI decreased sotorasib exposure by 57% under fed conditions and 42% under fasted conditions.
Quizartinib: (Major) Avoid concomitant use of sotorasib with quizartinib due to the risk of decreased quizartinib exposure which may reduce its efficacy. Quizartinib is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Coadministration with another moderate CYP3A inducer decreased the quizartinib overall exposure by 90%.
Rabeprazole: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as proton pump inhibitors (PPIs). Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with a PPI decreased sotorasib exposure by 57% under fed conditions and 42% under fasted conditions.
Ranitidine: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as H2-receptor antagonists. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with an H2-receptor antagonist decreased sotorasib exposure by 38% under fed conditions.
Ranolazine: (Contraindicated) Coadministration of ranolazine with sotorasib is contraindicated. Concomitant use may have an unpredictable effect on ranolazine exposure resulting in decreased ranolazine efficacy or an increase in ranolazine-related adverse effects. Ranolazine is a CYP3A and P-gp substrate and sotorasib is a moderate CYP3A inducer and P-gp inhibitor. Ranolazine use is contraindicated with moderate CYP3A inducers.
Relugolix: (Major) Avoid concomitant use of relugolix and oral sotorasib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is necessary, administer sotorasib at least six hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of sotorasib is required; if treatment is interrupted for more than seven days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-gp substrate and sotorasib is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral sotorasib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is necessary, administer sotorasib at least six hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of sotorasib is required; if treatment is interrupted for more than seven days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-gp substrate and sotorasib is a P-gp inhibitor. (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with sotorasib. Sotorasib may have an unpredictable effect on repotrectinib overall exposure and may decrease repotrectinib efficacy or increase the risk for repotrectinib-related adverse effects. Repotrectinib is a CYP3A and P-gp substrate; sotorasib is a moderate CYP3A inducer and P-gp inhibitor.
Rifampin: (Major) Avoid concurrent use of sotorasib and rifampin. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the AUC of sotorasib by 51%.
Rifapentine: (Major) Avoid concurrent use of sotorasib and rifapentine. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with sotorasib 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 sotorasib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rilpivirine: (Moderate) Coadministration of rilpivirine with sotorasib may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Rimegepant: (Major) Avoid coadministration of rimegepant with sotorasib; concurrent use may alter rimegepant exposure which may result in loss of efficacy or increased toxicity. Rimegepant is a CYP3A4 and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor.
Ripretinib: (Major) Avoid coadministration of ripretinib with sotorasib. If concomitant use is unavoidable, increase the frequency of ripretinib dosing from 150 mg once daily to 150 mg twice daily; monitor for clinical response and tolerability. Resume once daily dosing of ripretinib 14 days after discontinuation of sotorasib. Coadministration is predicted to decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease ripretinib anti-tumor activity. Ripretinib and DP-5439 are metabolized by CYP3A and sotorasib is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Ritonavir: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with sotorasib. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and sotorasib is a moderate CYP3A4 inducer.
Rosuvastatin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with sotorasib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and sotorasib is a BCRP inhibitor.
Rosuvastatin; Ezetimibe: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with sotorasib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and sotorasib is a BCRP inhibitor.
Saquinavir: (Moderate) Monitor for decreased efficacy or increased toxicity of saquinavir if concurrent use of sotorasib is necessary. Concurrent use may alter saquinavir plasma concentrations. Saquinavir is a CYP3A4 and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and P-gp inhibitor.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Segesterone Acetate; Ethinyl Estradiol: (Major) Women taking both estrogens and sotorasib should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed sotorasib. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of sotorasib. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on sotorasib, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and sotorasib is a moderate CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and sotorasib due to the risk of decreased selpercatinib exposure which may reduce its efficacy. Selpercatinib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selpercatinib exposure by 40% to 70%.
Selumetinib: (Major) Avoid coadministration of selumetinib and sotorasib due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with a moderate CYP3A4 inducer is predicted to decrease selumetinib exposure by approximately 38%.
Sildenafil: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with sotorasib is necessary as concurrent use may decrease sildenafil exposure. Sildenafil is a sensitive CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Population pharmacokinetic analysis indicates an approximately 3-fold increase in sildenafil clearance with concomitant use of weak CYP3A4 inducers.
Silodosin: (Major) Avoid coadministration of silodosin and sotorasib due to the potential for increased silodosin exposure. In vitro data indicate that silodosin is a P-glycoprotein substrate; sotorasib is a P-gp inhibitor.
Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sotorasib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; sotorasib is a P-gp inhibitor.
Siponimod: (Moderate) Concomitant use of siponimod and sotorasib is not recommended for patients with CYP2C9*1/*3 and *2/*3 genotypes due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; sotorasib is a moderate CYP3A4 inducer. Across different CYP2C9 genotypes, a moderate CYP3A4 inducer decreased the exposure of siponimod by up to 52% according to in silico evaluation.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of sotorasib. Concomitant use may alter sirolimus exposure resulting in decreased efficacy or increased risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and sotorasib is a moderate CYP3A inducer and P-gp inhibitor.
Sofosbuvir; Velpatasvir: (Major) Concomitant use of velpatasvir with sotorasib is not recommended due to the risk of decreased plasma concentrations of velpatasvir, which may result in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Concomitant use of velpatasvir with sotorasib is not recommended due to the risk of decreased plasma concentrations of velpatasvir, which may result in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Major) Concomitant use of voxilaprevir with sotorasib is not recommended due to the risk of decreased plasma concentrations of voxilaprevir, which may result in loss of antiviral efficacy. Voxilaprevir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Solifenacin: (Moderate) Monitor for decreased efficacy of solifenacin if coadministration with sotorasib is necessary. Solifenacin is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and sotorasib; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Physiologic-based pharmacokinetics (PBPK) simulations indicate that a moderate CYP3A4 inducer would decrease the sonidegib AUC by 56% if administered for 14 days and by 69% if the moderate CYP3A inducer is administered for more than 14 days.
St. John's Wort, Hypericum perforatum: (Major) Avoid concurrent use of sotorasib and St. John's Wort. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if sotorasib must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with sotorasib is necessary; consider increasing the dose of sufentanil injection as needed. If sotorasib is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate if coadministration with sotorasib is necessary; a tacrolimus dose adjustment may be needed. Concurrent administration may decrease tacrolimus concentrations. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; sotorasib is a moderate CYP3A4 inducer.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of sotorasib is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a P-gp and BCRP substrate; sotorasib is a P-gp and BCRP inhibitor.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with sotorasib as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Telmisartan; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with sotorasib is necessary. Amlodipine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with sotorasib is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and sotorasib is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with sotorasib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate. Sotorasib is a P-gp and BCRP inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with sotorasib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate. Sotorasib is a P-gp and BCRP inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with sotorasib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and sotorasib is a P-gp and BCRP inhibitor.
Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with sotorasib as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and sotorasib is a P-gp inhibitor.
Tipranavir: (Moderate) Monitor for decreased efficacy or increased toxicity of tipranavir if coadministered with sotorasib. Concurrent use may alter the plasma concentrations of tipranavir. Tipranavir is a CYP3A and P-gp substrate; sotorasib is a moderate CYP3A inducer and P-gp inhibitor.
Topotecan: (Major) Avoid coadministration of sotorasib with oral topotecan due to increased topotecan exposure; sotorasib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-gp and BCRP. Sotorasib is a P-gp and BCRP inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. 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.
Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with sotorasib is necessary; consider increasing the dose of tramadol as needed. If sotorasib is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with sotorasib is necessary; consider increasing the dose of tramadol as needed. If sotorasib is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Tramadol is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Ubrogepant: (Major) Avoid concurrent use of sotorasib and ubrogepant due to unpredictable effects. Coadministration may alter the exposure of ubrogepant resulting in decreased efficacy or increased toxicity. Ubrogepant is a CYP3A4, BCRP, and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and a BCRP and P-gp inhibitor.
Venetoclax: (Major) Avoid concurrent use of sotorasib and venetoclax due to unpredictable effects. Coadministration may alter the exposure of venetoclax resulting in decreased efficacy or increased toxicity. Venetoclax is a CYP3A and P-gp substrate; sotorasib is a moderate CYP3A inducer and P-gp inhibitor.
Vincristine Liposomal: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of sotorasib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and sotorasib is a P-gp inhibitor.
Vincristine: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of sotorasib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and sotorasib is a P-gp inhibitor.
Voclosporin: (Major) Avoid coadministration of voclosporin with sotorasib. Coadministration may decrease voclosporin exposure resulting in decreased efficacy. Voclosporin is a sensitive CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Coadministration with moderate CYP3A4 inducers is predicted to decrease voclosporin exposure by 70%.
Vonoprazan: (Major) Avoid concomitant use of vonoprazan and sotorasib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Additionally, vonoprazan reduces intragastric acidity, which may decrease the absorption of sotorasib reducing its efficacy. Vonoprazan is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of vonoprazan and sotorasib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Additionally, vonoprazan reduces intragastric acidity, which may decrease the absorption of sotorasib reducing its efficacy. Vonoprazan is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of vonoprazan and sotorasib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Additionally, vonoprazan reduces intragastric acidity, which may decrease the absorption of sotorasib reducing its efficacy. Vonoprazan is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer. (Major) Consider alternatives to clarithromycin if treatment with sotorasib is necessary as concurrent use may decrease efficacy of clarithromycin. Clarithromycin is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. Inducers of CYP3A enzymes decrease plasma concentrations of clarithromycin while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. There have been spontaneous or published reports of CYP3A-based interactions of clarithromycin with another CYP3A4 inducer.
Voxelotor: (Major) Avoid coadministration of voxelotor and sotorasib as concurrent use may decrease voxelotor exposure and lead to reduced efficacy. If coadministration is unavoidable, increase voxelotor dosage to 2,000 mg PO once daily in patients 12 years and older. In patients 4 to 11 years old, weight-based dosage adjustments are recommended; consult product labeling for specific recommendations. Voxelotor is a substrate of CYP3A; sotorasib is a moderate CYP3A inducer. Coadministration of voxelotor with a moderate CYP3A inducer is predicted to decrease voxelotor exposure by up to 24%.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with sotorasib is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. Sotorasib is a CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zanubrutinib: (Major) Avoid concurrent use of zanubrutinib and sotorasib due to the risk of decreased zanubrutinib exposure which may reduce its efficacy. If concomitant use is necessary, increase the zanubrutinib dose to 320 mg twice daily and monitor response. Resume the previous dose of zanubrutinib if sotorasib is discontinued. Zanubrutinib is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Concomitant use with another moderate CYP3A inducer decreased zanubrutinib exposure by 44%.
Sotorasib is a KRAS G12C inhibitor, with minimal detectable off-target activity. KRAS, a member of the RAS GTPase family, is the most frequently mutated oncogene in human cancers and encodes a GTPase that cycles between active (guanosine triphosphate [GTP]-bound) and inactive (guanosine diphosphate [GDP]-bound) states to regulate signal transduction. The glycine-to-cysteine mutation at position 12 favors the active form of the KRAS protein, resulting in KRAS that is predominantly bound to GTP and enhanced tumor cell proliferation and survival. The mutated cysteine resides next to a pocket of the switch II region (P2) that is only present in the inactive GDP-bound conformation of KRAS. Sotorasib forms an irreversible, covalent bond with the unique cysteine of KRAS G12C, locking the protein in the inactive GDP-bound state that prevents downstream signaling without affecting wild-type KRAS. It blocked KRAS signaling, inhibited cell growth, and promoted apoptosis only in KRAS G12C tumor cell lines. In mouse tumor xenograft models, sotorasib treatment led to tumor regressions and prolonged survival; it was also associated with antitumor immunity in KRAS G12C models.
Sotorasib is administered orally. It is 89% bound to plasma proteins in vitro. The mean volume of distribution of sotorasib at steady-state is 211 liters (CV, 135%). The mean terminal elimination half-life is 5 hours (standard deviation, 2), with steady-state achieved within 22 days. The steady-state apparent clearance is 26.2 liters/hour (CV, 76%). Accumulation was not observed after repeat doses of sotorasib, with a mean accumulation ratio of 0.56 (CV, 59%). After a single radiolabeled dose of sotorasib, 74% of the dose was recovered in feces (53% unchanged) and 6% in the urine (1% unchanged).
Affected cytochrome P450 (CYP) isoenzymes and drug transporters: CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP)
Sotorasib is mainly metabolized via nonenzymatic conjugation and oxidative metabolism with CYP3A enzymes. Concomitant use with repeat doses of rifampin (a strong CYP3A4 inducer) decreased the Cmax and AUC of sotorasib by 35% and 51%, respectively; administration with a single dose of rifampin (an OATP1B1/1B3 inhibitor) did not have a clinically meaningful effect on sotorasib exposure. Similarly, administration with itraconazole (a strong CYP3A4 inhibitor) did not have a clinically meaningful effect on sotorasib exposure. Sotorasib is also a moderate CYP3A4 inducer, a P-gp inhibitor, and a BCRP inhibitor. In vitro, sotorasib may induce CYP2C8, CYP2C9, and CYP2B6; it may inhibit BCRP in vitro.
-Route-Specific Pharmacokinetics
Oral Route
The median time to peak plasma concentrations of sotorasib (Tmax) is 1 hour. Sotorasib exhibits nonlinear, time-dependent pharmacokinetics of a dose range of 180 mg to 960 mg once daily with similar systemic exposure (AUC and Cmax) across doses at steady-state. The systemic exposure of sotorasib was comparable between film-coated tablets and film-coated tablets predispersed in water and administered under fasting conditions. The AUC of sotorasib increased by 25% when administered with a high-fat, high-calorie meal (approximately 800 to 1,000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively) compared with administration under fasted conditions.
-Special Populations
Hepatic Impairment
The AUC of sotorasib decreased by 25% in subjects with moderate hepatic impairment (Child-Pugh B) and increased by 4% in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function.
Renal Impairment
Mild to moderate renal impairment (eGFR 30 mL/min/1.73m2 or higher) did not have a clinically meaningful effect on the pharmacokinetics of sotorasib. The effect of severe renal impairment on the pharmacokinetics of sotorasib has not been studied.
Geriatric
Age (28 to 86 years) did not have a clinically meaningful effect on the pharmacokinetics of sotorasib.
Gender Differences
Sex did not have a clinically meaningful effect on the pharmacokinetics of sotorasib.
Ethnic Differences
Race (White, Black, and Asian) did not have a clinically meaningful effect on the pharmacokinetics of sotorasib.
Obesity
Body weight (36.8 kg to 157.9 kg) did not have a clinically meaningful effect on the pharmacokinetics of sotorasib.
Other
The line of therapy or ECOG performance status (0 or 1) did not have a clinically meaningful effect on the pharmacokinetics of sotorasib.