Ripretinib is a tyrosine kinase inhibitor that works in many mutant KIT and PDGFRA kinases found in tumor cells. It is indicated for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Cardiac dysfunction (e.g., decreased ejection fraction and heart failure) has been reported; evaluate cardiac function prior to and during therapy as clinically indicated.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Take ripretinib with or without food at the same time each day.
-Swallow tablets whole.
-If a dose is missed and the patient takes ripretinib once daily, give it right away if it is within 8 hours of the scheduled dose; if more than 8 hours have passed, skip the dose and give the next dose at the regularly scheduled time.
-If a dose is missed and the patient takes ripretinib twice daily (i.e., dose adjustment for coadministration with moderate CYP3A inducers), give it right away if it is within 4 hours of the scheduled dose; if more than 4 hours have passed, skip the dose and give the next dose at the regularly scheduled time.
-If vomiting occurs, do not administer an additional dose of ripretinib; continue regular administration with the next scheduled dose.
Dermatologic adverse events including alopecia (52% vs. 4.7%), palmar-plantar erythrodysesthesia (hand and foot syndrome) (21% vs. 0%), dry skin/xerosis (13% vs. 7%), and pruritus (11% vs. 4.7%) were reported more often in patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) compared with placebo (n = 43) in a randomized trial. Rash and acneiform rash were each reported in fewer than 10% of patients in this trial. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop grade 2 or higher palmar-plantar erythrodysesthesia. Photosensitivity reactions occurred in 0.6% of all patients treated with ripretinib (n = 621). Patients should be advised to limit direct ultraviolet exposure by using sunscreen or protective clothing during treatment and for at least 1 week after discontinuation treatment.
New primary malignancy, specifically skin cancer, including cutaneous squamous-cell carcinoma (cuSCC) (7%), keratoacanthoma (1.9%), and melanoma (0.9%) were reported in patients who received ripretinib in a pooled safety analysis (n = 351). Additionally, cuSCC (4.7%) and melanoma (2.4%) occurred in patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) in a randomized trial. Perform dermatologic evaluations prior to starting therapy and routinely during treatment. The median time to onset of cuSCC was 4.6 months (range, 3.8 to 6 months) in the randomized trial. Excise and evaluate the pathology of suspicious skin lesions; continue ripretinib at the same dose.
Hypertension was reported in 14% of patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) compared with 4.7% of patients who received placebo (n = 43) in a randomized trial; grade 3 hypertension occurred in 7% and 0% of patients in the ripretinib and placebo arms, respectively. Monitor patient blood pressure prior to starting ripretinib and as clinically indicated during treatment; initiate or adjust antihypertensive therapy as appropriate. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop grade 3 or 4 hypertension.
Cardiotoxicity including cardiac dysfunction (1.7%; grade 3, 1.1%) including heart failure, acute left ventricular failure, diastolic dysfunction, and ventricular hypertrophy) and cardiac ischemic events including cardiac arrest, acute coronary syndrome, and myocardial infarction (MI) occurred in patients who received ripretinib in a pooled safety analysis (n = 351). In this analysis, grade 3 decreased ejection fraction was reported in 3.4% of 263 patients who had a baseline and at least 1 post-baseline echocardiogram; fatal cases of cardiac arrest and MI were also reported. Additionally, heart failure occurred in 1.2% of patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) in a randomized trial; grade 3 decreased ejection fraction was reported in 2.6% of 77 patients who had a baseline and at least 1 post-baseline echocardiogram. Evaluate patient ejection fraction via echocardiogram or MUGA scan prior to starting ripretinib and as clinically indicated during treatment. Permanently discontinue ripretinib in patients who develop grade 3 or 4 left ventricular systolic dysfunction.
Gastrointestinal adverse events including nausea (39% vs. 12%; grade 3 or 4, 3.5% vs. 0%), abdominal pain (36% vs. 30%; grade 3 or 4, 7% vs. 2.3%), constipation (34% vs. 19%; grade 3 or 4, 1.2% vs. 0%), diarrhea (28% vs. 14%; grade 3 or 4, 1.2% vs. 0%), decreased appetite/anorexia (27% vs. 21%; grade 3 or 4, 1.2% vs. 2.3%), vomiting (21% vs. 7%; grade 3 or 4, 3.5% vs. 0%), and stomatitis (11% vs. 0%) were reported more often in patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) compared with placebo (n = 43) in a randomized trial.
Musculoskeletal adverse events including myalgia (32% vs. 12%; grade 3 or 4, 1.2% vs. 0%), increased creatine phosphokinase (CPK) levels (21% vs. 10%; grade 3 or 4, 1.2% vs. 0%), arthralgia (18% vs. 4.7%), and muscle cramps/spasms (15% vs. 4.7%) were reported more often in patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) compared with placebo (n = 43) in a randomized trial. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop grade 2 or higher myalgia or arthralgia.
Peripheral edema was reported in 17% of patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) compared with 7% of patients who received placebo (n = 43) in a randomized trial; grade 3 or 4 peripheral edema occurred in 1.2% and 0% respectively.
Fatigue was reported in 42% of patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) compared with 23% of patients who received placebo (n = 43) in a randomized trial; grade 3 or 4 fatigue occurred in 3.5% and 2.3% of patients, respectively. Asthenia occurred less often in the ripretinib (13%; grade 3 or 4, 1.2%) arm compared with the placebo (14%; grade 3 or 4, 4.7%) arm.
Weight loss was reported in 19% of patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) compared with 12% of patients who received placebo (n = 43) in a randomized trial.
Headache was reported in 19% of patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) compared with 4.7% of patients who received placebo (n = 43) in a randomized trial.
Dyspnea was reported in 13% of patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) compared with 0% of patients who received placebo (n = 43) in a randomized trial.
Prolonged bleeding time including increased activated partial thromboplastin time (35% vs. 9%) and increased INR (21% vs. 15%; grade 3 or 4, 3.8% vs. 0%) were reported more often in patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) compared with placebo (n = 43) in a randomized trial.
Decreased neutrophil count/neutropenia occurred in 10% of patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) compared with 2.5% of patients who received placebo (n = 43) in a randomized trial. Serious cases of anemia were reported in 3.5% of ripretinib-treated patients.
Increased lipase level (32% vs. 13%; grade 3 or 4, 7% vs. 8%) and increased serum amylase level/hyperamylasemia (13% vs. 5%; grade 3 or 4, 1.2% vs. 0%) were reported more often in patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) compared with placebo (n = 43) in a randomized trial.
Electrolyte abnormalities including decreased phosphate level/hypophosphatemia (26% vs. 2.5%; grade 3 or 4, 4.9% vs. 0%), decreased calcium level/hypocalcemia (23% vs. 8%), and decreased sodium level/hyponatremia (17% vs. 10%; grade 3 or 4, 2.4% vs. 2.5%) were reported more often in patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) compared with placebo (n = 43) in a randomized trial.
Elevated hepatic enzymes, specifically increased ALT level (12% vs. 5%; grade 3 or 4, 1.2% vs. 0%) and increased blood bilirubin level/hyperbilirubinemia (22% vs. 5%) were reported more often in patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) compared with placebo (n = 43) in a randomized trial.
Nephrotoxicity, specifically increased serum creatinine level, occurred less often in patients with advanced gastrointestinal stromal tumor who received ripretinib (16%) compared with placebo (18%) in a randomized trial (n = 128).
Increased triglycerides level/hypertriglyceridemia was reported in 26% of patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) compared with 23% of patients who received placebo (n = 43) in a randomized trial; grade 3 or 4 hypertriglyceridemia occurred in 2.4% and 0% of patients, respectively.
Peripheral neuropathy occurred in fewer than 10% of patients with advanced gastrointestinal stromal tumor who received ripretinib (n = 85) in a randomized trial.
Serious rash including palmar-plantar erythrodysesthesia (hand and foot syndrome) has been reported with ripretinib therapy. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop grade 2 or higher palmar-plantar erythrodysesthesia.
Musculoskeletal adverse events including myalgia and arthralgia have been reported with ripretinib therapy. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop grade 2 or higher myalgia or arthralgia.
New primary malignancy (e.g., cutaneous squamous-cell carcinoma, keratoacanthoma, and melanoma) has been reported with ripretinib therapy. Perform dermatologic evaluations prior to starting therapy and routinely during treatment. Excise and evaluate the pathology of suspicious skin lesions; continue ripretinib at the same dose.
Hypertension has been reported with ripretinib therapy. Monitor patient blood pressure prior to starting ripretinib and as clinically indicated during treatment; initiate or adjust antihypertensive therapy as appropriate. Do not start ripretinib in patients with uncontrolled hypertension. Therapy interruption, dose reduction, or discontinuation may be necessary in patients who develop grade 3 or 4 hypertension.
Cardiac dysfunction (e.g., heart failure, acute left ventricular failure, diastolic dysfunction, and ventricular hypertrophy) and cardiac ischemic events (e.g., cardiac arrest, myocardial infarction (MI), and acute coronary syndrome) have occurred with ripretinib therapy; therefore, use ripretinib with caution in patients with cardiac disease. Fatal cases of cardiac arrest and MI have been reported. The safety of using ripretinib in patients with a baseline ejection fraction below 50% has not been assessed. Evaluate patient ejection fraction via echocardiogram or MUGA scan prior to starting ripretinib and as clinically indicated during treatment. Permanently discontinue ripretinib in patients who develop grade 3 or 4 left ventricular systolic dysfunction.
Patients who receive ripretinib may be at risk for developing impaired wound healing complications because impaired wound healing has been reported with other drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Hold ripretinib therapy for at least 1 week prior to elective surgery and at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming ripretinib in patients after resolution of wound healing complications has not been assessed.
Ripretinib may cause photosensitivity. Patients should be advised to limit sunlight (UV) exposure by using sunscreen or protective clothing during treatment and for at least 1 week after discontinuation treatment.
Ripretinib may cause fetal harm when administered during pregnancy based on its mechanism of action and data from animal studies. Women who are pregnant should be apprised of the potential hazard to the fetus. Females of reproductive potential should avoid pregnancy during ripretinib therapy. In embryo-fetal development studies in rats, malformations primarily associated with the cardiovascular and skeletal systems (e.g., interrupted or retroesophageal aortic arch and retroesophageal subclavian artery; fusion of the exoccipital bone to the first cervical vertebra; branched and fused ribs; anomalies of the cervical, thoracic, caudal, and sacral vertebrae; absent forepaw phalanges; and absent metacarpals) and an increased incidence of anatomic variations were reported with ripretinib dosing that resulted in approximately one-half the exposure at the recommended human dose. Additionally, a total loss of pregnancy (following ripretinib dosing that resulted in about 3.5 times the human exposure at the recommended dose) and increased post-implantation loss and decreased fetal body weights (following ripretinib dosing that resulted in approximately 2.1 times the human exposure at the recommended dose) occurred in pregnant rabbits.
Counsel patients about the reproductive risk and contraception requirements during ripretinib treatment. Females of reproductive potential should receive pregnancy testing prior to starting ripretinib. These patients should avoid pregnancy and use effective contraception during and for 1 week after the final ripretinib dose. Women who become pregnant while receiving ripretinib should be apprised of the potential hazard to the fetus. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should also use effective contraception during and for 1 week after the final ripretinib dose. There is a risk of infertility in male patients who receive ripretinib, based on data from animal studies.
It is not known if ripretinib or its metabolites are secreted in human milk or if it has effects on the breast-fed child or on milk production. Due to the risk of serious adverse reactions in nursing children, women should discontinue breast-feeding during ripretinib therapy and for 1 week after the last dose.
For the treatment of gastrointestinal stromal tumors (GIST):
NOTE: The FDA has designated ripretinib as an orphan drug for this indication.
-for the treatment of advanced GIST in patients who have received prior treatment with 3 or more kinase inhibitors, including imatinib:
Oral dosage:
Adults: 150 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. The median progression-free survival time was 6.3 months in patients with unresectable, locally advanced or metastatic GIST who received ripretinib (n = 85) compared with 1 month (n = 44) in patients who received placebo (hazard ratio = 0.15; 95% CI, 0.09 to 0.25; p less than 0.0001) in a multinational, randomized, double-blind trial (the INVICTUS trial). The median overall survival time was 15.1 months and 6.6 months in patients in the ripretinib and placebo arms (HR = 0.36; 95% CI, 0.21 to 0.62), respectively. Crossover to the ripretinib therapy occurred in 66% of patients in the placebo arm after disease progression. The overall response rates were 9% and 0% in patients who received ripretinib and placebo, respectively. Patients (median age, 60 years; range, 29 to 83 years) in this study had received 3 or more prior therapies for GIST.
Therapeutic Drug Monitoring:
Dose Adjustments for Treatment-Related Toxicities
NOTE: Permanently discontinue therapy in patients unable to tolerate ripretinib 100 mg PO once daily.
Palmar-Plantar Erythrodysesthesia Syndrome (PPES)
Grade 2 toxicity: Hold ripretinib until the toxicity resolves to grade 1 or less or to baseline. Resume therapy at the same dose if the toxicity resolves within 7 days; otherwise, resume therapy at a reduced ripretinib dose of 100 mg PO once daily. Consider increasing the ripretinib dose back to 150 mg PO once daily if PPES remains at grade 1 or less or at baseline for at least 28 days. For recurrent PPES, hold ripretinib until the toxicity resolves to grade 1 or less or to baseline and resume at the reduced dose of 100 mg PO once daily regardless of time to improvement.
Grade 3 toxicity: Hold ripretinib for at least 7 days (maximum of 28 days) or until the toxicity resolves to grade 1 or less or to baseline. Resume therapy at a reduced ripretinib dose of 100 mg PO once daily. Consider increasing the ripretinib dose back to 150 mg PO once daily if PPES remains at grade 1 or less or at baseline for at least 28 days.
Hypertension
Grade 3 toxicity: For symptomatic hypertension, hold ripretinib until symptoms have resolved and blood pressure is controlled. If blood pressure is controlled to grade 1 or less or to baseline, resume therapy at the same dose; otherwise, resume therapy at a reduced ripretinib dose of 100 mg PO once daily. For recurrent grade 3 hypertension, hold ripretinib until symptoms have resolved and blood pressure is controlled and resume at the reduced dose of 100 mg PO once daily.
Grade 4 toxicity: Permanently discontinue ripretinib therapy.
Left Ventricular Systolic Dysfunction
Grade 3 or 4 toxicity: Permanently discontinue ripretinib therapy.
Arthralgia or Myalgia
Grade 2 toxicity: Hold ripretinib until the toxicity resolves to grade 1 or less or to baseline. Resume therapy at the same dose if the toxicity resolves within 7 days; otherwise, resume therapy at a reduced ripretinib dose of 100 mg PO once daily. Consider increasing the ripretinib dose back to 150 mg PO once daily if toxicity remains at grade 1 or less or at baseline for at least 28 days. For recurrent arthralgia or myalgia, hold ripretinib until the toxicity resolves to grade 1 or less or to baseline and resume at the reduced dose of 100 mg PO once daily regardless of time to improvement.
Grade 3 toxicity: Hold ripretinib for at least 7 days (maximum of 28 days) or until the toxicity resolves to grade 1 or less or to baseline. Resume therapy at a reduced ripretinib dose of 100 mg PO once daily. Consider increasing the ripretinib dose back to 150 mg PO once daily if the toxicity remains at grade 1 or less or at baseline for at least 28 days.
Other Adverse Reactions
Grade 3 or 4 toxicity: Hold ripretinib until the toxicity resolves to grade 1 or less or to baseline (or a maximum of 28 days). Resume therapy at a reduced ripretinib dose of 100 mg PO once daily or permanently discontinue therapy. Consider increasing the ripretinib dose back to 150 mg PO once daily if toxicity does not recur for at least 28 days. Permanently discontinue ripretinib therapy if the grade 3 or 4 toxicity recurs.
Maximum Dosage Limits:
-Adults
150 mg PO once daily.
-Geriatric
150 mg PO once daily.
-Adolescents
Safety and effectiveness have not been established.
-Children
Safety and effectiveness have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustment is recommended for patients with hepatic impairment (Child-Pugh A, B, or C).
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Adagrasib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with adagrasib. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A and adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ripretinib and DP-5439 exposure by 99%.
Amobarbital: (Major) Avoid coadministration of ripretinib with amobarbital. 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 amobarbital. 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 amobarbital is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with clarithromycin. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Apalutamide: (Major) Avoid coadministration of ripretinib with apalutamide. Coadministration may 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 CYP3A4 and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid coadministration of ripretinib with butalbital. 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 butalbital. 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 butalbital is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Atazanavir: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with atazanavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Atazanavir; Cobicistat: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with atazanavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%. (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with cobicistat. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Bexarotene: (Major) Avoid coadministration of ripretinib with bexarotene. 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 bexarotene. 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 bexarotene is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Bosentan: (Major) Avoid coadministration of ripretinib with bosentan. 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 bosentan. 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 bosentan is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Butalbital; Acetaminophen: (Major) Avoid coadministration of ripretinib with butalbital. 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 butalbital. 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 butalbital is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid coadministration of ripretinib with butalbital. 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 butalbital. 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 butalbital is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid coadministration of ripretinib with butalbital. 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 butalbital. 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 butalbital is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid coadministration of ripretinib with butalbital. 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 butalbital. 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 butalbital is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Carbamazepine: (Major) Avoid coadministration of ripretinib with carbamazepine. Coadministration may 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 CYP3A4 and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Cenobamate: (Major) Avoid coadministration of ripretinib with cenobamate. 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 cenobamate. 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 cenobamate is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Ceritinib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with ceritinib. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Chloramphenicol: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with chloramphenicol. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
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.
Clarithromycin: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with clarithromycin. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Cobicistat: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with cobicistat. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Dabrafenib: (Major) Avoid coadministration of ripretinib with dabrafenib. 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 dabrafenib. 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 dabrafenib is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Darunavir: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with darunavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Darunavir; Cobicistat: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with cobicistat. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%. (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with darunavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with cobicistat. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%. (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with darunavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Delavirdine: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with delavirdine. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
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.
Efavirenz: (Major) Avoid coadministration of ripretinib with efavirenz. 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 efavirenz. 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 efavirenz is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of ripretinib with efavirenz. 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 efavirenz. 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 efavirenz is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of ripretinib with efavirenz. 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 efavirenz. 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 efavirenz is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Elagolix: (Major) Avoid coadministration of ripretinib with elagolix. 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 elagolix. 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 elagolix is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid coadministration of ripretinib with elagolix. 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 elagolix. 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 elagolix is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with cobicistat. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with cobicistat. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Encorafenib: (Major) Avoid coadministration of ripretinib with encorafenib. Coadministration may 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 encorafenib is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Enzalutamide: (Major) Avoid coadministration of ripretinib with enzalutamide. Coadministration may 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 CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Eslicarbazepine: (Major) Avoid coadministration of ripretinib with eslicarbazepine. 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 eslicarbazepine. 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 eslicarbazepine is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Etravirine: (Major) Avoid coadministration of ripretinib with etravirine. 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 etravirine. 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 etravirine is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Fosphenytoin: (Major) Avoid coadministration of ripretinib with fosphenytoin. Coadministration may 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 CYP3A4 and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Grapefruit juice: (Major) Advise patients to avoid grapefruit juice while taking Ripretinib. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Idelalisib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with idelalisib. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Indinavir: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with indinavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of ripretinib with rifampin. Coadministration may 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 CYP3A4 and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Isoniazid, INH; Rifampin: (Major) Avoid coadministration of ripretinib with rifampin. Coadministration may 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 CYP3A4 and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Itraconazole: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with itraconazole. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and itraconazole is a strong CYP3A4 inhibitor. Coadministration with itraconazole increased ripretinib and DP-5439 exposure by 99%.
Ketoconazole: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with ketoconazole. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with clarithromycin. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Levoketoconazole: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with ketoconazole. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and ketoconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Lonafarnib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with lonafarnib. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Lopinavir; Ritonavir: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with ritonavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Lorlatinib: (Major) Avoid coadministration of ripretinib with lorlatinib. 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 lorlatinib. 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 lorlatinib is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of ripretinib with lumacaftor; ivacaftor. Coadministration may 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 lumacaftor is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Lumacaftor; Ivacaftor: (Major) Avoid coadministration of ripretinib with lumacaftor; ivacaftor. Coadministration may 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 lumacaftor is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Mavacamten: (Major) Avoid coadministration of ripretinib with mavacamten. 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 mavacamten. 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 mavacamten is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Methohexital: (Major) Avoid coadministration of ripretinib with methohexital. 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 methohexital. 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 methohexital is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Mifepristone: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with mifepristone. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and mifepristone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Mitotane: (Major) Avoid coadministration of ripretinib with mitotane. Coadministration may 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 CYP3A4 and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Nafcillin: (Major) Avoid coadministration of ripretinib with nafcillin. 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 nafcillin. 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 nafcillin is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Nefazodone: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with nefazodone. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Nelfinavir: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with nelfinavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Nirmatrelvir; Ritonavir: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with ritonavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid coadministration of ripretinib with rifabutin. 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 rifabutin. 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 rifabutin is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Pexidartinib: (Major) Avoid coadministration of ripretinib with pexidartinib. 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 pexidartinib. 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 pexidartinib is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Phenobarbital: (Major) Avoid coadministration of ripretinib with phenobarbital. Coadministration may 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 CYP3A4 and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of ripretinib with phenobarbital. Coadministration may 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 CYP3A4 and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Phenytoin: (Major) Avoid coadministration of ripretinib with phenytoin. Coadministration may 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 CYP3A4 and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Posaconazole: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with posaconazole. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and posaconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Primidone: (Major) Avoid coadministration of ripretinib with primidone. Coadministration may 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 CYP3A4 and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Repotrectinib: (Major) Avoid coadministration of ripretinib with repotrectinib. 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 repotrectinib. 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 repotrectinib is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Ribociclib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with ribociclib. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Ribociclib; Letrozole: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with ribociclib. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Rifabutin: (Major) Avoid coadministration of ripretinib with rifabutin. 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 rifabutin. 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 rifabutin is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Rifampin: (Major) Avoid coadministration of ripretinib with rifampin. Coadministration may 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 CYP3A4 and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Rifapentine: (Major) Avoid coadministration of ripretinib with rifapentine. Coadministration may 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 CYP3A4 and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Ritonavir: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with ritonavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Saquinavir: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with saquinavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
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.
Secobarbital: (Major) Avoid coadministration of ripretinib with secobarbital. 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 secobarbital. 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 secobarbital is a moderate CYP3A inducer. Drug interaction modeling studies suggest coadministration with a moderate CYP3A inducer may decrease ripretinib exposure by 56%.
Sotorasib: (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%.
St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of ripretinib with St. John's Wort. Coadministration may 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 CYP3A4 and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Tipranavir: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with tipranavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Tucatinib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with tucatinib. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with clarithromycin. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Voriconazole: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with voriconazole. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Ripretinib is a switch-control type-2 kinase inhibitor that inhibits gastrointestinal stromal tumor (GIST) cells with wild-type, primary, and secondary KIT and platelet derived growth factor receptor A (PDGFRA) mutations. Switch control kinase inhibitors work by forcing the activation loop into an inactive conformation; they inhibit drug-resistant active kinases and can turn off an already active kinase. In vitro, ripretinib inhibited KIT mutations V654A exon 13, T670I exon 14, D816H exon 17, and D816V exon 17 and the PDGFRA mutation D842V exon 18. Additionally, the active metabolite of ripretinib, DP-5439, exhibited a similar kinase inhibitory profile. KIT phosphorylation inhibition by ripretinib was demonstrated in GIST cell lines, including D816V and exon 11, 13, 11/13, and 11/17 mutations. Broad KIT or PDGFRA phosphorylation inhibition by ripretinib also occurred in transfected cell lines with clinically identified primary and drug-resistant mutations, including KIT exons 9, 9/13, 9/17, 9/18, and 11/18 mutations and the PDGFRA mutations N659K exon 14 and D842V exon 18. Ripretinib also inhibits other kinases in vitro, including PDGFRB, TIE2, VEGFR2, and BRAF.
Ripretinib is administered orally. It is 99.8% bound to human serum albumin and 99.4% bound to alfa-1 acid glycoprotein. Following a single oral dose of ripretinib 150 mg in healthy subjects, the mean steady-state apparent volume of distribution was 307 L (coefficient of variation (CV), 39%) for ripretinib and 507 L (CV, 57%) for its active metabolite, DP-5439; the mean plasma elimination half-lives of ripretinib and DP-5439 were 14.8 hours (CV, 30%) and 17.8 hours (CV, 23%), respectively. The mean apparent clearance was 15.3 L/hour (CV, 45%) for ripretinib and 17.5 L/hour (CV, 63%) for DP-5439. For ripretinib, 34% of the dose was excreted in the feces and 0.02% was excreted in the urine. For DP-5439, 6% and 0.1% of the dose was excreted in the feces and urine, respectively.
Affected cytochrome P450 isoenzymes or transporters: CYP3A4, CYP2C8, CYP2D6, CYP2E1, BCRP, P-gp, MATE1
Ripretinib and its active metabolite, DP-5439, are primarily metabolized by CYP3A4, and to a lesser extent by CYP2C8 and CYP2D6 (and CYP2E1 in DP-5439 only); they are also both P-gp and BCRP substrates. Plasma exposure was not significantly affected when ripretinib was administered with a proton pump inhibitor (pantoprazole). In vitro, ripretinib and DP-5439 are inhibitors of CYP2C8 and Breast Cancer Resistance Protein (BCRP). Ripretinib is an inhibitor of P-gp and BCRP; DP-5439 inhibits BCRP and Multidrug And Toxin Extrusion Protein 1 (MATE1).
-Route-Specific Pharmacokinetics
Oral Route
At the recommended dose of 150 mg PO once daily, the mean steady-state Cmax value was 761 ng/mL (coefficient of variation (CV), 32%) for ripretinib and 804 ng/mL (CV, 46%) for the active metabolite, DP-5439; the mean steady-state AUC(0-12h) values were 5,678 ng X hours/mL (CV, 32%) and 7,138 ng X hours/mL (CV, 44%), respectively. For ripretinib, the AUC(0-24h) value increased proportionally, the Cmax value was less than dose proportional, and the accumulation ratio was 1.7 (CV, 55%) following a single dose over a range of 20 to 250 mg. Over this same dose range, both the DP-5439 AUC(0-24h) and Cmax values were less than dose proportional and the accumulation ratio was 5.29 (CV, 49%). Steady state levels occurred at 14 days for both ripretinib and DP-5439; the median Tmax occurred at 4 hours and 15.6 hours for the parent drug and active metabolite, respectively.
Effects of food: There were no clinically significant differences in the Cmax and AUC(0-24h) values when ripretinib was administered with a high-fat meal (consisting of approximately 150 calories from protein, 250 calories from carbohydrate, and 500-600 calories from fat) compared with the fasted state.
-Special Populations
Hepatic Impairment
There were no clinically significant changes in the AUC and Cmax of ripretinib in subjects with mild hepatic impairment compared to matched healthy subjects. In subjects with moderate hepatic impairment, the AUC of ripretinib increased 2-fold while the Cmax was unchanged; the combined AUC of ripretinib and DP-5439 increased 1.5-fold. The AUC of ripretinib increased 2.6-fold and the Cmax decreased by 24% compared to healthy subjects in subjects with severe hepatic impairment; the combined AUC of ripretinib and DP-5439 increased by 1.4-fold. These increases in exposure in subjects with hepatic impairment are unlikely to be clinically relevant based on the known safety profile of ripretinib.
Renal Impairment
Mild to moderate renal impairment (creatinine clearance (CrCl), 30 to 89 mL/min) has no clinically significant impact on the pharmacokinetic (PK) values of ripretinib. The effect of severe renal impairment (CrCl, 15 to 29 mL/min) on the PK values of ripretinib has not been evaluated.
Geriatric
Age (range, 19 to 87 years) has no clinically significant impact on the pharmacokinetic values of ripretinib.
Gender Differences
Gender has no clinically significant impact on the pharmacokinetic values of ripretinib.
Ethnic Differences
Ethnicity (White, Black, Asian) has no clinically significant impact on the pharmacokinetic values of ripretinib.
Obesity
Body weight (39 to 138 kg) has no clinically significant impact on the pharmacokinetic values of ripretinib.
Other
Tumor type (GIST or other solid tumors) and prior gastrectomy have no clinically significant impact on the pharmacokinetic values of ripretinib.