Pirtobrutinib is a Bruton tyrosine kinase (BTK) inhibitor approved for the treatment of adult patients with relapsed or refractory mantle cell lymphoma after at least 2 lines of systemic therapy, including a BTK inhibitor. It is also indicated for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma after at least 2 lines of prior therapy, including a BTK inhibitor and a BCL-2 inhibitor. Fatal and serious infections and bleeding events have been reported with pirtobrutinib therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Minimal/Low
-Administer prn antiemetics as necessary.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Take pirtobrutinib orally at the same time each day with or without food.
-Swallow tablets whole with water; do not cut, crush, or chew tablets.
-If a dose is missed by more than 12 hours, do not make up the dose and take the next dose as scheduled.
Falls were reported in 14% (grade 3 or 4, 0.9%) of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma who received pirtobrutinib (n = 110) in a multicohort trial.
Elevated lipase level that worsened from baseline was reported in 12% (grade 3 or 4, 4.4%) of pirtobrutinib-treated patients with mantle cell lymphoma (n = 128) and 21% (grade 3 or 4, 7%) of pirtobrutinib-treated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 110) in a multicohort trial.
Grade 3 or higher infection (24%; grade 5, 4.4%) including pneumonia (14%), sepsis (16%), and febrile neutropenia (4%) occurred in patients with hematologic malignancies who received pirtobrutinib in a pooled safety analysis (n = 593); COVID-19 was reported in 22% of pirtobrutinib-treated patients. Evaluate patients with signs or symptoms of infection promptly; treat as medically appropriate. Dosage adjustment, therapy interruption, or therapy discontinuation may be necessary if a severe infection occurs. In a multicohort trial, infectious adverse events that were reported with pirtobrutinib therapy in patients with mantle cell lymphoma (MCL; n = 128) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 110) included pneumonia (MCL: 16%; grade 3 or 4, 14%; CLL/SLL: 27%; grade 3 or 4, 16%), upper respiratory tract infection (MCL: 10%; grade 3 or 4, 0.8%; CLL/SLL: 13%; grade 3 or 4, 2.7%), lower respiratory tract infection (CLL/SLL: less than 10%), respiratory tract infection (CLL/SLL: 11%; grade 3 or 4, 1.8%), COVID19 (CLL/SLL: 28%; grade 3 or 4, 7%), urinary tract infection (MCL: less than 10%; CLL/SLL: less than 10%), and herpes virus infection (MCL: less than 10%; CLL/SLL: less than 10%). Fatal infections (MCL; 4.7%; CLL/SLL, 8%), including fatal COVID-19 infection and sepsis, were also reported.
Bleeding (17%) and bruising (21%) were reported in patients with hematologic malignancies who received pirtobrutinib in a pooled safety analysis (n = 593). Grade 3 or higher bleeding or any central nervous system bleeding (major bleeding) including GI bleeding occurred in 3% of patients and fatal bleeding occurred in 0.3% of patients. Dosage adjustment, therapy interruption, or therapy discontinuation may be necessary if severe bleeding occurs. In a multicohort trial, bleeding events that were reported with pirtobrutinib therapy in patients with mantle cell lymphoma (MCL; n = 128) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 110) included bleeding (MCL: 11%; grade 3 or 4, 3.1%; CLL/SLL: 22%; grade 3 or 4, 2.7%) and bruising (MCL: 16%; CLL/SLL: 36%). Fatal bleeding occurred in 1 CLL/SLL patient with MCL. The term bleeding included intracranial bleeding and GI bleeding in patients with CLL/SLL.
Cough occurred in 20% of patients with hematologic malignancies who received pirtobrutinib in a pooled safety analysis (n = 593). In a multicohort trial, respiratory adverse events that were reported with pirtobrutinib therapy in patients with mantle cell lymphoma (MCL; n = 128) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 110) included dyspnea (MCL: 17%; grade 3 or 4, 2.3%; CLL/SLL: 22%; grade 3 or 4, 2.7%) and cough (MCL: 14%; CLL/SLL: 33%).
Decreased neutrophil count/neutropenia (46%; grade 3 or 4, 26%), decreased hemoglobin level/anemia (39%; grade 3 or 4, 12%), decreased platelet count/thrombocytopenia (29%; grade 3 or 4, 12%), and decreased lymphocyte count/lymphopenia (31%) occurred in patients with hematologic malignancies who received pirtobrutinib in a pooled safety analysis (n = 593). Dosage adjustment, therapy interruption, or therapy discontinuation may be necessary if severe hematologic toxicity occurs. In a multicohort trial, hematologic laboratory abnormalities that worsened from baseline with pirtobrutinib therapy in patients with mantle cell lymphoma (MCL; n = 128) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 110) included decreased hemoglobin level (MCL: 42%; grade 3 or 4, 9%; CLL/SLL: 48%; grade 3 or 4, 19%), decreased platelet count (MCL: 39%; grade 3 or 4, 14%; CLL/SLL: 30%; grade 3 or 4, 15%), decreased neutrophil count (MCL: 36%; grade 3 or 4, 16%; CLL/SLL: 63%; grade 3 or 4, 45%), and decreased lymphocyte count (MCL: 32%; grade 3 or 4, 15%; CLL/SLL: 23%; grade 3 or 4, 8%).
Atrial fibrillation or atrial flutter (3.2%; grade 3 or 4, 1.5%) and other serious cardiac arrhythmias (0.5%) such as supraventricular tachycardia (SVT) and cardiac arrest occurred in patients with hematologic malignancies who received pirtobrutinib in a pooled safety analysis (n = 593). Dosage adjustment, therapy interruption, or therapy discontinuation may be necessary if cardiac arrhythmia occurs. Supraventricular tachycardias (e.g., sinus tachycardia and atrial fibrillation) were reported in 10% (grade 3 or 4, 5%) of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma who received pirtobrutinib (n = 110) in a multicohort trial.
New primary malignancy (9%) including non-melanoma skin cancer (4.6%) occurred in patients with hematologic malignancies who received pirtobrutinib in a pooled safety analysis (n = 593). Other new primary malignancies that have been reported with pirtobrutinib include solid tumors (e.g., genitourinary cancer and breast cancer) and melanoma. New primary malignancy was reported in 13% (grade 3 or 4, 2.7%) of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma who received pirtobrutinib (n = 110) in a multicohort trial. There was 1 fatality due to metastatic melanoma.
Fatigue occurred in 32% of patients with hematologic malignancies who received pirtobrutinib in a pooled safety analysis (n = 593). Fatigue was reported in 29% (grade 3 or 4, 1.6%) of pirtobrutinib-treated patients with mantle cell lymphoma (n = 128) and 36% (grade 3 or 4, 2.7%) of pirtobrutinib-treated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 110) in a multicohort trial.
Edema was reported in 18% (grade 3 or 4, 0.8%) of pirtobrutinib-treated patients with mantle cell lymphoma (n = 128) and 21% of pirtobrutinib-treated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 110) in a multicohort trial.
Fever was reported in 13% of pirtobrutinib-treated patients with mantle cell lymphoma (n = 128) and 20% (grade 3 or 4, 2.7%) of pirtobrutinib-treated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 110) in a multicohort trial.
Musculoskeletal pain occurred in 30% of patients with hematologic malignancies who received pirtobrutinib in a pooled safety analysis (n = 593). In a multicohort trial, musculoskeletal adverse events that were reported with pirtobrutinib therapy in patients with mantle cell lymphoma (MCL; n = 128) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 110) included musculoskeletal pain (MCL: 27%; grade 3 or 4, 3.9%; CLL/SLL: 32%; grade 3 or 4, 0.9%) and arthritis or arthralgia (MCL: 16%; CLL/SLL: 19%; grade 3 or 4, 1.8%).
Diarrhea occurred in 24% of patients with hematologic malignancies who received pirtobrutinib in a pooled safety analysis (n = 593). In a multicohort trial, gastrointestinal adverse events that were reported with pirtobrutinib therapy in patients with mantle cell lymphoma (MCL; n = 128) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 110) included diarrhea (MCL: 19%; CLL/SLL: 26%), constipation (MCL: 13%; CLL/SLL: 14%), abdominal pain (MCL: 11%; grade 3 or 4, 0.8%; CLL/SLL: 25%; grade 3 or 4, 2.7%), nausea (MCL: 11%; CLL/SLL: 21%), decreased appetite/anorexia (CLL/SLL: 12%), and mucositis/oral ulceration (CLL/SLL: 12%; grade 3 or 4, 0.9%).
In a multicohort trial, neurological adverse events that were reported with pirtobrutinib therapy in patients with mantle cell lymphoma (MCL; n = 128) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 110) included peripheral neuropathy (MCL: 14%; grade 3 or 4, 0.8%; CLL/SLL: 16%; grade 3 or 4, 3.6%), dizziness (MCL: 10%; CLL/SLL: 15%), and headache (MCL: less than 10%; CLL/SLL: 20%; grade 3 or 4, 0.9%). Neurological changes (e.g., memory impairment, confusion, encephalopathy, mental status changes) occurred in 12% (grade 3 or 4, 2.7%) of pirtobrutinib-treated patients with CLL/SLL. Additionally, memory changes occurred in less than 10% of patients with MCL.
Rash was reported in 14% of pirtobrutinib-treated patients with mantle cell lymphoma (n = 128) and 19% (grade 3 or 4, 0.9%) of pirtobrutinib-treated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 110) in a multicohort trial.
In a multicohort trial, electrolyte abnormalities that worsened from baseline that were reported with pirtobrutinib therapy in patients with mantle cell lymphoma (MCL; n = 128) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 110) included decreased calcium level/hypocalcemia (MCL: 19%; grade 3 or 4, 1.6%; CLL/SLL: 40%; grade 3 or 4, 2.8%), decreased potassium level/hypokalemia (MCL: 13%; grade 3 or 4, 1.6%), increased potassium level/hyperkalemia (MCL: 11%; grade 3 or 4, 0.8%), and decreased sodium level/hyponatremia (MCL: 13%; CLL/SLL: 30%).
In a multicohort trial, elevated hepatic enzymes that worsened from baseline that were reported with pirtobrutinib therapy in patients with mantle cell lymphoma (MCL; n = 128) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 110) included increased ALT level (MCL: 11%; grade 3 or 4, 1.6%; CLL/SLL: 23%; grade 3 or 4, 2.8%), increased AST level (MCL: 17%; grade 3 or 4, 1.6%; CLL/SLL: 23%; grade 3 or 4, 1.9%), and increased alkaline phosphatase level (MCL: 11%; CLL/SLL: 21%).
Nephrotoxicity, specifically increased serum creatinine that worsened from baseline, was reported in 30% (grade 3 or 4, 1.6%) of pirtobrutinib-treated patients with mantle cell lymphoma (n = 128) and 23% of pirtobrutinib-treated patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) (n = 110) in a multicohort trial. Renal insufficiency (e.g., renal failure, chronic kidney disease, acute kidney injury) occurred in 12% (grade 3 or 4, 6%) of patients with CLL/SLL.
Tumor lysis syndrome (TLS) occurred in less than 10% of patients with mantle cell lymphoma (n = 128) and chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 110) who received pirtobrutinib in a multicohort trial.
Visual impairment/vision changes occurred in less than 10% of patients with mantle cell lymphoma (n = 128) and chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 110) who received pirtobrutinib in a multicohort trial.
Hypertension was reported in 12% (grade 3 or 4, 5%) of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma who received pirtobrutinib (n = 110) in a multicohort trial.
Patients with asymptomatic lymphocytosis should continue pirtobrutinib therapy. A temporary lymphocytosis (increased absolute lymphocyte count of 50% or more from baseline and a post baseline value of 5,000 cells/microliter or more) was reported in 34% of pirtobrutinib-treated patients with mantle cell lymphoma (MCL; n = 128) and 64% of pirtobrutinib-treated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 110) in a multicohort trial. In patients with MCL, the median time to onset and duration were 1.1 and 11 weeks, respectively; 75% of cases occurred within the first 2.1 weeks. In patients with CLL/SLL, the median time to onset and duration were 1.1 and 19 weeks, respectively; 75% of cases occurred within the first 1.1 weeks.
Insomnia was reported in 14% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma who received pirtobrutinib (n = 110) in a clinical trial.
Serious infection (e.g., sepsis, Pneumocystis jirovecii pneumonia, and fungal infection) has been reported with pirtobrutinib therapy; some cases were fatal. Evaluate patients for signs and symptoms of infection and treat promptly. Consider infection prophylaxis in patients at risk for infections. Dosage adjustment, therapy interruption, or therapy discontinuation may be necessary if a severe infection occurs.
Major bleeding events have been reported with pirtobrutinib therapy, including GI bleeding. Monitor patients for signs and symptoms of bleeding. Dosage adjustment, therapy interruption, or therapy discontinuation may be necessary if severe bleeding occurs. Patients receiving concomitant antithrombotic therapy may be at increased risk for major bleeding; therefore, evaluate the risk/benefit of using concomitant antithrombotic therapy. Evaluate the risk/benefit of stopping pirtobrutinib 3 to 7 days pre- and post-surgery depending on the type of surgery and the risk of bleeding.
Severe cytopenias (e.g., neutropenia, anemia, and thrombocytopenia) have been reported with pirtobrutinib therapy. Monitor complete blood counts regularly. Dosage adjustment, therapy interruption, or therapy discontinuation may be necessary if severe hematologic toxicity occurs.
Cardiac arrhythmias (e.g., atrial fibrillation or flutter) have been reported with pirtobrutinib therapy. Patients with cardiac disease or risk factors, such as hypertension or previous arrhythmias, may be at increased risk. Monitor for signs and symptoms of arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea) and manage appropriately. Dosage adjustment, therapy interruption, or therapy discontinuation may be necessary if cardiac arrhythmia occurs.
New primary malignancy (e.g., skin cancer, solid tumors) has been reported with pirtobrutinib therapy. Monitor patients for signs and symptoms of new primary malignancy. Advise patients to avoid sunlight (UV) exposure and to use sun protection.
Reduce the initial dosage in patients with severe (estimated glomerular filtration rate [eGFR], 15 to 29 mL/min) renal impairment. No initial dosage adjustment is needed necessary for patients with mild or moderate (eGFR, 30 to 89 mL/min) renal impairment.
In the pooled safety population in patients with hematologic malignancies, grade 3 or higher adverse reactions occurred more often in geriatric patients aged 65 years and older who received pirtobrutinib therapy compared with patients younger than 65 years of age.
Pirtobrutinib may cause fetal harm if administered during pregnancy based on data from animal studies. Patients of reproductive potential should avoid pregnancy during pirtobrutinib therapy. Pregnant patients should be apprised of the potential hazard to the fetus. In pregnant rats, decreased fetal body weights, malformations (i.e., absent or abnormal ureters and kidneys, malpositioned ovaries and misshapen uterus, and misshapen sternebrae), and embryo-fetal mortality were observed following pirtobrunib doses that resulted in maternal systemic exposures that were approximately 3 times the human exposure (at the recommended dose).
Counsel patients about the reproductive risk and contraception requirements during pirtobrutinib treatment. Pregnancy testing should be performed prior to starting pirtobrutinib in patients of reproductive potential. These patients should use effective contraception and avoid pregnancy during and for 1 week after pirtobrutinib therapy. Patients who become pregnant while receiving pirtobrutinib should be apprised of the potential hazard to the fetus.
It is not known if pirtobrutinib is excreted in human milk or if it has effects on the breast-fed child or on milk production. Due to the risk of serious adverse effects in nursing children, patients should discontinue breast-feeding during pirtobrutinib therapy and for 1 week after the last dose.
For the treatment of mantle cell lymphoma (MCL):
NOTE: Pirtobrutinib is designated as an orphan drug by the FDA for this indication.
-for the treatment of relapsed or refractory MCL after at least 2 lines of systemic therapy, including a BTK inhibitor:
Oral dosage:
Adults: 200 mg orally once daily until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, and/or discontinuation may be necessary if severe toxicity occurs. The independent review committee (IRC)-assessed overall response rate was 50% (complete response rate, 13%) in 120 patients with MCL who received pirtobrutinib as monotherapy in a phase 1/2 (BRUIN) trial. The median duration of response was 8.3 months. Patients (median age, 71 years; range, 46 to 88 years) in this trial had received a median of 3 (range, 1 to 9) prior treatments which included a BTK inhibitor.
For the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL):
NOTE: Pirtobrutinib is designated as an orphan drug by the FDA for this indication.
-for the treatment of CLL/SLL after at least 2 lines of prior therapy, including a BTK inhibitor and a BCL-2 inhibitor:
Oral dosage:
Adults: 200 mg orally once daily until disease progression. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Therapy interruption, dose reduction, and/or discontinuation may be necessary if severe toxicity occurs. The independent review committee (IRC)-assessed overall response rate was 72% (all partial responses) in 108 patients with CLL or SLL who received pirtobrutinib as monotherapy in a multicohort, phase 1/2 (BRUIN) trial. At a median follow-up time of 15.7 months, the median duration of response was 12.2 months. Patients (median age, 68 years; range, 41 to 88 years) in this trial had received a median of 5 (range, 2 to 11) prior treatments which included a BTK inhibitor and a BCL-2 inhibitor.
Therapeutic Drug Monitoring:
Management of Treatment-Related Toxicity
Dosage Guidance
First occurrence:* 200 mg PO once daily.
Second occurrence: 100 mg once daily.
Third occurrence: 50 mg once daily.
Fourth occurrence: Discontinue pirtobrutinib therapy.
*Evaluate benefit versus risk of therapy before resuming treatment at the same dose for grade 4 non-hematological toxicity.
Hematologic Toxicity
Absolute neutrophil count (ANC) of 0.5 to less than 1 x 109 cells/L with fever and/or infection, ANC less than 0.5 x 109 cells/L (lasting 7 or more days), platelet count of 25 to less than 50 x 109; cells/L with bleeding, or platelet count less than 25 x 109 cells/L: Hold pirtobrutinib therapy. Upon recovery to grade 1 or baseline, resume pirtobrutinib at the dosage that is recommended based on the adverse reaction occurrence.
Non-hematologic Toxicity
Grade 3 or greater toxicity: Hold pirtobrutinib therapy. Upon recovery to grade 1 or baseline, resume pirtobrutinib at the dosage that is recommended based on the adverse reaction occurrence.
Maximum Dosage Limits:
-Adults
200 mg/day PO.
-Geriatric
200 mg/day PO.
-Adolescents
Safety and efficacy not established.
-Children
Safety and efficacy not established.
-Infants
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Mild (total bilirubin level at the upper limit of normal (ULN) or less and AST level more than the ULN, or total bilirubin level more than 1 to 1.5 times the ULN and any AST level), moderate (total bilirubin level more than 1.5 to 3 times the ULN and any AST level), or severe (total bilirubin level more than 3 times the ULN and any AST level) hepatic impairment: No initial dosage adjustment necessary.
Patients with Renal Impairment Dosing
Mild or moderate renal impairment (estimated glomerular filtration rate [eGFR], 30 to 89 mL/min): No initial dosage adjustment is necessary.
Severe renal impairment (eGFR, 15 to 29 mL/min): Reduce dose to 100 mg once daily if the current dose is 200 mg once daily, otherwise reduce dose by 50 mg.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with pirtobrutinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and pirtobrutinib is a P-gp and BCRP inhibitor.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. If pirtobrutinib is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with pirtobrutinib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If pirtobrutinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Pirtobrutinib is a weak inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with pirtobrutinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of pirtobrutinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If pirtobrutinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Pirtobrutinib is a weak inhibitor of CYP3A.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like pirtobrutinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If pirtobrutinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. If pirtobrutinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like pirtobrutinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone.
Adagrasib: (Major) Avoid concomitant use of pirtobrutinib and adagrasib due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of adagrasib use. Resume the previous dose of pirtobrutinib after adagrasib is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Afatinib: (Moderate) If the concomitant use of pirtobrutinib 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 pirtobrutinib. 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 pirtobrutinib is a P-gp inhibitor. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC of afatinib was 119% when coadministered with the same P-gp inhibitor, and 111% when the inhibitor was administered 6 hours after afatinib.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. If pirtobrutinib is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A substrate, and coadministration with CYP3A inhibitors like pirtobrutinib can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil.
Alpelisib: (Major) Avoid coadministration of alpelisib with pirtobrutinib 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 pirtobrutinib is a BCRP inhibitor.
Alprazolam: (Major) Avoid coadministration of alprazolam and pirtobrutinib due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with pirtobrutinib, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pirtobrutinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; pirtobrutinib is a P-gp and BCRP inhibitor.
Amobarbital: (Major) Avoid concurrent use of pirtobrutinib and barbiturates due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of pirtobrutinib and clarithromycin due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of clarithromycin use. Resume the previous dose of pirtobrutinib after clarithromycin is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Apalutamide: (Major) Avoid concurrent use of pirtobrutinib and apalutamide due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of pirtobrutinib. Patients receiving both a CYP2D6 inhibitor plus pirtobrutinib may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; pirtobrutinib is a weak CYP3A inhibitor.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concurrent use of pirtobrutinib and barbiturates due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with pirtobrutinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of pirtobrutinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If pirtobrutinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Pirtobrutinib is a weak inhibitor of CYP3A.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. If pirtobrutinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like pirtobrutinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone.
Atazanavir: (Major) Avoid concomitant use of pirtobrutinib and atazanavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of atazanavir use. Resume the previous dose of pirtobrutinib after atazanavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Atazanavir; Cobicistat: (Major) Avoid concomitant use of pirtobrutinib and atazanavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of atazanavir use. Resume the previous dose of pirtobrutinib after atazanavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%. (Major) Avoid concomitant use of pirtobrutinib and cobicistat due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of cobicistat use. Resume the previous dose of pirtobrutinib after cobicistat is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pirtobrutinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; pirtobrutinib is a P-gp and BCRP inhibitor.
Barbiturates: (Major) Avoid concurrent use of pirtobrutinib and barbiturates due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of pirtobrutinib with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and pirtobrutinib is a CYP2C19 inhibitor.
Benzhydrocodone; Acetaminophen: (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like pirtobrutinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of benzhydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If pirtobrutinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to benzhydrocodone.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving pirtobrutinib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving pirtobrutinib. 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; pirtobrutinib is a P-gp inhibitor. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2 to 3-fold.
Bexarotene: (Major) Avoid concurrent use of pirtobrutinib and bexarotene 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 bexarotene is a moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with pirtobrutinib 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 and pirtobrutinib is a P-gp and BCRP inhibitor.
Bosentan: (Major) Avoid concurrent use of pirtobrutinib and bosentan 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 bosentan is a moderate CYP3A inducer. Concomitant use reduced pirtobrutinib overall exposure by 27%.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with pirtobrutinib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor.
Buprenorphine: (Moderate) Concomitant use of buprenorphine and pirtobrutinib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when pirtobrutinib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping pirtobrutinib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If pirtobrutinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and pirtobrutinib is a CYP3A inhibitor.
Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and pirtobrutinib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when pirtobrutinib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping pirtobrutinib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If pirtobrutinib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and pirtobrutinib is a CYP3A inhibitor.
Butalbital; Acetaminophen: (Major) Avoid concurrent use of pirtobrutinib and barbiturates due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concurrent use of pirtobrutinib and barbiturates due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concurrent use of pirtobrutinib and barbiturates due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%. (Moderate) Concomitant use of codeine with pirtobrutinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of pirtobrutinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If pirtobrutinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Pirtobrutinib is a weak inhibitor of CYP3A.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concurrent use of pirtobrutinib and barbiturates due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%. (Moderate) Concomitant use of codeine with pirtobrutinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of pirtobrutinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If pirtobrutinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Pirtobrutinib is a weak inhibitor of CYP3A.
Carbamazepine: (Major) Avoid concurrent use of pirtobrutinib and carbamazepine due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. The exposure of carbamazepine may also be increased. Pirtobrutinib is a CYP3A substrate and CYP3A inhibitor and carbamazepine is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with pirtobrutinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of pirtobrutinib, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Cenobamate: (Major) Avoid concurrent use of pirtobrutinib and cenobamate 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 cenobamate is a moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Ceritinib: (Major) Avoid concomitant use of pirtobrutinib and ceritinib due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of ceritinib use. Resume the previous dose of pirtobrutinib after ceritinib is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Chloramphenicol: (Major) Avoid concomitant use of pirtobrutinib and chloramphenicol due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of chloramphenicol use. Resume the previous dose of pirtobrutinib after chloramphenicol is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with pirtobrutinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of pirtobrutinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If pirtobrutinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Pirtobrutinib is a weak inhibitor of CYP3A.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like pirtobrutinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If pirtobrutinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Cisapride: (Major) Avoid concomitant use of cisapride and pirtobrutinib; use increases cisapride exposure and the risk for adverse effects such as QT/QTc prolongation and torsade de pointes (TdP). Cisapride is a CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor. Concomitant use of cisapride with CYP3A inhibitors is disallowed under the Propulsid Limited Access Program.
Citalopram: (Moderate) Limit the dose of citalopram to 20 mg/day if coadministered with pirtobrutinib. Concurrent use may increase citalopram exposure increasing the risk of QT prolongation. Citalopram is a sensitive CYP2C19 substrate; pirtobrutinib is a weak inhibitor of CYP2C19.
Clarithromycin: (Major) Avoid concomitant use of pirtobrutinib and clarithromycin due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of clarithromycin use. Resume the previous dose of pirtobrutinib after clarithromycin is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Clopidogrel: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of pirtobrutinib. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; pirtobrutinib is a CYP2C19 inhibitor.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with pirtobrutinib and monitor for adverse reactions. If pirtobrutinib is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A. Pirtobrutinib is a weak CYP3A inhibitor.
Cobicistat: (Major) Avoid concomitant use of pirtobrutinib and cobicistat due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of cobicistat use. Resume the previous dose of pirtobrutinib after cobicistat is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Cobimetinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with pirtobrutinib is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-gp substrate; pirtobrutinib is a P-gp inhibitor.
Codeine: (Moderate) Concomitant use of codeine with pirtobrutinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of pirtobrutinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If pirtobrutinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Pirtobrutinib is a weak inhibitor of CYP3A.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with pirtobrutinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of pirtobrutinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If pirtobrutinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Pirtobrutinib is a weak inhibitor of CYP3A.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with pirtobrutinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of pirtobrutinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If pirtobrutinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Pirtobrutinib is a weak inhibitor of CYP3A.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with pirtobrutinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of pirtobrutinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If pirtobrutinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Pirtobrutinib is a weak inhibitor of CYP3A.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with pirtobrutinib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of pirtobrutinib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If pirtobrutinib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Pirtobrutinib is a weak inhibitor of CYP3A.
Colchicine: (Major) Avoid concomitant use of colchicine and pirtobrutinib 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 pirtobrutinib is a P-gp inhibitor.
Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with pirtobrutinib is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A and P-gp substrate and pirtobrutinib is a P-gp and weak CYP3A inhibitor.
Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with pirtobrutinib is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/minute. Avoid coadministration in patients with CrCl less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCl less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-gp substrate and pirtobrutinib is a P-gp inhibitor.
Dabrafenib: (Major) Avoid concurrent use of pirtobrutinib and dabrafenib 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 dabrafenib is a moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Daprodustat: (Major) Reduce the initial daprodustat dose by half during concomitant use of pirtobrutinib unless the daprodustat dose is already 1 mg. Monitor hemoglobin and further adjust the daprodustat dose as appropriate. Concomitant use may increase daprodustat exposure and the risk for daprodustat-related adverse reactions. Daprodustat is a CYP2C8 substrate and pirtobrutinib is a moderate CYP2C8 inhibitor. Concomitant use with a moderate CYP2C8 inhibitor is expected to increase daprodustat overall exposure by approximately 4-fold.
Darunavir: (Major) Avoid concomitant use of pirtobrutinib and darunavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of darunavir use. Resume the previous dose of pirtobrutinib after darunavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Darunavir; Cobicistat: (Major) Avoid concomitant use of pirtobrutinib and cobicistat due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of cobicistat use. Resume the previous dose of pirtobrutinib after cobicistat is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%. (Major) Avoid concomitant use of pirtobrutinib and darunavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of darunavir use. Resume the previous dose of pirtobrutinib after darunavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid concomitant use of pirtobrutinib and cobicistat due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of cobicistat use. Resume the previous dose of pirtobrutinib after cobicistat is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%. (Major) Avoid concomitant use of pirtobrutinib and darunavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of darunavir use. Resume the previous dose of pirtobrutinib after darunavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%. (Moderate) Coadministration of tenofovir alafenamide with pirtobrutinib 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 and pirtobrutinib is a P-gp and BCRP inhibitor.
Delavirdine: (Major) Avoid concomitant use of pirtobrutinib and delavirdine due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of delavirdine use. Resume the previous dose of pirtobrutinib after delavirdine is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with pirtobrutinib is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A and CYP2C19 substrate and pirtobrutinib is a CYP3A and CYP2C19 inhibitor.
Digoxin: (Moderate) Increase monitoring of serum digoxin concentrations and watch for potential signs and symptoms of clinical toxicity when starting, adjusting, or discontinuing pirtobrutinib. Concurrent use may increase digoxin exposure. Digoxin is a P-gp substrate with a narrow therapeutic index and pirtobrutinib is a P-gp inhibitor. Concomitant use was observed to increase digoxin overall exposure by 35%.
Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with pirtobrutinib is necessary as concurrent use may increase disopyramide exposure. Disopyramide is a CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when disopyramide was coadministered with moderate and strong CYP3A inhibitors.
Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with pirtobrutinib is necessary as concurrent use may increase dofetilide exposure. Pirtobrutinib is a weak CYP3A inhibitor. Dofetilide is a minor CYP3A substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A inhibitors may increase the risk of arrhythmia (torsade de pointes).
Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with pirtobrutinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and pirtobrutinib is a P-gp and BCRP inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with pirtobrutinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and pirtobrutinib is a P-gp and BCRP inhibitor.
Dolutegravir; Rilpivirine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with pirtobrutinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and pirtobrutinib is a P-gp and BCRP inhibitor.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with pirtobrutinib 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 pirtobrutinib is a P-gp and BCRP inhibitor.
Doxepin: (Moderate) Monitor for an increase in doxepin-related adverse reactions if concomitant use of pirtobrutinib is necessary. Concomitant use may increase doxepin exposure; doxepin is primarily metabolized by CYP2C19 and CYP2D6 and pirtobrutinib is a CYP2C19 inhibitor.
Doxorubicin Liposomal: (Major) Avoid coadministration of pirtobrutinib with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and pirtobrutinib is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of pirtobrutinib with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and pirtobrutinib is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Edoxaban: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of pirtobrutinib is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and pirtobrutinib 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 pirtobrutinib. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of pirtobrutinib. Increased concentrations of edoxaban may occur during concomitant use of pirtobrutinib; monitor for increased adverse effects of edoxaban.
Efavirenz: (Major) Avoid concurrent use of pirtobrutinib and efavirenz 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 efavirenz is a moderate CYP3A inducer. Concomitant use reduced pirtobrutinib overall exposure by 49%.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of pirtobrutinib and efavirenz 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 efavirenz is a moderate CYP3A inducer. Concomitant use reduced pirtobrutinib overall exposure by 49%. (Moderate) Coadministration of tenofovir disoproxil fumarate with pirtobrutinib 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 pirtobrutinib is a P-gp and BCRP inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid concurrent use of pirtobrutinib and efavirenz 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 efavirenz is a moderate CYP3A inducer. Concomitant use reduced pirtobrutinib overall exposure by 49%. (Moderate) Coadministration of tenofovir disoproxil fumarate with pirtobrutinib 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 pirtobrutinib is a P-gp and BCRP inhibitor.
Elagolix: (Major) Avoid concurrent use of pirtobrutinib and elagolix 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 elagolix is a moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid concurrent use of pirtobrutinib and elagolix 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 elagolix is a moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Eliglustat: (Major) Coadministration of eliglustat and pirtobrutinib is not recommended in poor CYP2D6 metabolizers (PMs). In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Eliglustat is a CYP3A and CYP2D6 substrate; pirtobrutinib is a weak CYP3A inhibitor. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid concomitant use of pirtobrutinib and cobicistat due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of cobicistat use. Resume the previous dose of pirtobrutinib after cobicistat is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%. (Moderate) Coadministration of tenofovir alafenamide with pirtobrutinib 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 and pirtobrutinib is a P-gp and BCRP inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of pirtobrutinib and cobicistat due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of cobicistat use. Resume the previous dose of pirtobrutinib after cobicistat is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%. (Moderate) Coadministration of tenofovir disoproxil fumarate with pirtobrutinib 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 pirtobrutinib is a P-gp and BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with pirtobrutinib 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 and pirtobrutinib is a P-gp and BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with pirtobrutinib 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 pirtobrutinib is a P-gp and BCRP inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with pirtobrutinib 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 and pirtobrutinib is a P-gp and BCRP inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with pirtobrutinib 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 pirtobrutinib is a P-gp and BCRP inhibitor.
Encorafenib: (Major) Avoid concurrent use of pirtobrutinib and encorafenib due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Enzalutamide: (Major) Avoid concurrent use of pirtobrutinib and enzalutamide due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Eslicarbazepine: (Major) Avoid concurrent use of pirtobrutinib and eslicarbazepine 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 eslicarbazepine is a moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Etrasimod: (Major) Avoid concomitant use of etrasimod and pirtobrutinib in CYP2C9 poor metabolizers due to the risk for increased etrasimod exposure which may increase the risk for adverse effects. Etrasimod is a CYP2C9 and CYP2C8 substrate and pirtobrutinib is a moderate CYP2C8 inhibitor.
Etravirine: (Major) Avoid concurrent use of pirtobrutinib and etravirine 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 etravirine is a moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with pirtobrutinib is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-gp substrate and pirtobrutinib is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pirtobrutinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; pirtobrutinib is a P-gp inhibitor.
Felodipine: (Moderate) Concurrent use of felodipine and pirtobrutinib should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor. Concurrent use of another weak CYP3A inhibitor increased felodipine AUC and Cmax by approximately 50%.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. If pirtobrutinib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like pirtobrutinib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If pirtobrutinib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or pirtobrutinib; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A inhibitors, including pirtobrutinib, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the potential outcomes of combination therapy with multiple weak CYP3A inhibitors and flibanserin should be discussed with the patient.
Fosphenytoin: (Major) Avoid concurrent use of pirtobrutinib and fosphenytoin due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. The exposure of fosphenytoin may also be increased. Pirtobrutinib is a CYP3A substrate and CYP2C19 inhibitor; phenytoin is a CYP2C19 substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and pirtobrutinib as increased plasma concentrations of glecaprevir may occur resulting in increased risk of glecaprevir-related adverse events. Glecaprevir is a substrate of P-gp and BCRP and pirtobrutinib is a P-gp and BCRP inhibitor. (Moderate) Monitor for an increase in pibrentasvir-related adverse effects if concomitant use of pirtobrutinib is necessary. Concomitant use may increase pibrentasvir exposure. Pibrentasvir is a substrate of P-gp and BCRP and pirtobrutinib is a P-gp and BCRP inhibitor.
Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during pirtobrutinib treatment due to the risk of increased pirtobrutinib exposure and adverse reactions. Pirtobrutinib is a CYP3A substrate and grapefruit juice is a strong CYP3A inhibitor.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like pirtobrutinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If pirtobrutinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like pirtobrutinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If pirtobrutinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like pirtobrutinib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If pirtobrutinib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. If pirtobrutinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like pirtobrutinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone.
Idelalisib: (Major) Avoid concomitant use of pirtobrutinib and idelalisib due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of idelalisib use. Resume the previous dose of pirtobrutinib after idelalisib is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Indinavir: (Major) Avoid concomitant use of pirtobrutinib and indinavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of indinavir use. Resume the previous dose of pirtobrutinib after indinavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and indinavir is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concurrent use of pirtobrutinib and rifampin due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use reduced pirtobrutinib overall exposure by 71%.
Isoniazid, INH; Rifampin: (Major) Avoid concurrent use of pirtobrutinib and rifampin due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use reduced pirtobrutinib overall exposure by 71%.
Isradipine: (Minor) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with pirtobrutinib is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor.
Itraconazole: (Major) Avoid concomitant use of pirtobrutinib and itraconazole due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of itraconazole use. Resume the previous dose of pirtobrutinib after itraconazole is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Concomitant increased pirtobrutinib overall exposure by 49%.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of pirtobrutinib is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor.
Ketoconazole: (Major) Avoid concomitant use of pirtobrutinib and ketoconazole due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of ketoconazole use. Resume the previous dose of pirtobrutinib after ketoconazole is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with pirtobrutinib 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 pirtobrutinib is a P-gp and BCRP inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of pirtobrutinib and clarithromycin due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of clarithromycin use. Resume the previous dose of pirtobrutinib after clarithromycin is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with pirtobrutinib is necessary. Lapatinib is a P-gp substrate and pirtobrutinib is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
Lefamulin: (Major) Avoid coadministration of pirtobrutinib with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; pirtobrutinib may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and pirtobrutinib is a P-gp inhibitor.
Lemborexant: (Major) Limit the dose of lemborexant to 5 mg PO once daily if coadministered with pirtobrutinib as concomitant use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A substrate; pirtobrutinib is a weak CYP3A inhibitor. Coadministration with a weak CYP3A inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Letermovir: (Major) Avoid concomitant use of pirtobrutinib and combination letermovir plus cyclosporine due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of combination letermovir plus cyclosporine use. Resume the previous dose of pirtobrutinib after combination letermovir plus cyclosporine is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and combination letermovir plus cyclosporine is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Levoketoconazole: (Major) Avoid concomitant use of pirtobrutinib and ketoconazole due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of ketoconazole use. Resume the previous dose of pirtobrutinib after ketoconazole is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with pirtobrutinib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with pirtobrutinib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with pirtobrutinib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor.
Lomitapide: (Major) Decrease the dose of lomitapide by one-half not to exceed 30 mg/day PO if coadministration with pirtobrutinib is necessary. Concomitant use may significantly increase the serum concentration of lomitapide. Pirtobrutinib is a weak CYP3A inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A inhibitors.
Lonafarnib: (Major) Avoid concomitant use of pirtobrutinib and lonafarnib due to the risk of increased exposure of both drugs which may increase the risk for adverse effects. If concomitant use is necessary, decrease the dosage of both drugs and closely monitor patients for adverse reactions. Reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of lonafarnib use. Resume the previous dose of pirtobrutinib after lonafarnib is discontinued for 5 half-lives. Reduce to or continue lonafarnib at a dosage of 115 mg/m2 and resume previous lonafarnib dosage 14 days after discontinuing pirtobrutinib. Pirtobrutinib is a CYP3A substrate and weak CYP3A inhibitor and lonafarnib is a sensitive CYP3A substrate and strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
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 pirtobrutinib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and pirtobrutinib 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 pirtobrutinib. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and pirtobrutinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Major) Avoid concomitant use of pirtobrutinib and ritonavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of ritonavir use. Resume the previous dose of pirtobrutinib after ritonavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Lorlatinib: (Major) Avoid concurrent use of pirtobrutinib and lorlatinib 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 lorlatinib is a moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pirtobrutinib is necessary. Concomitant use may increase lovastatin exposure. Lovastatin is a P-gp substrate; pirtobrutinib is a P-gp inhibitor.
Lumacaftor; Ivacaftor: (Major) Avoid concurrent use of pirtobrutinib and combination lumacaftor; ivacaftor due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and combination lumacaftor; ivacaftor is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Lumacaftor; Ivacaftor: (Major) Avoid concurrent use of pirtobrutinib and combination lumacaftor; ivacaftor due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and combination lumacaftor; ivacaftor is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with pirtobrutinib is necessary. Concomitant use may increase maraviroc exposure. Maraviroc is a P-gp substrate; pirtobrutinib is a P-gp inhibitor.
Mavacamten: (Major) Avoid concurrent use of pirtobrutinib and mavacamten due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. The exposure of mavacamten may also be increased. If concomitant use is necessary, dose adjustments of both drugs are needed. If the current pirtobrutinib 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. Reduce the mavacamten dose by 1 level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients receiving mavacamten and starting pirtobrutinib therapy. Avoid initiation of pirtobrutinib in patients who are on stable treatment with mavacamten 2.5 mg per day because a lower dose of mavacamten is not available. Initiate mavacamten at the recommended starting dose of 5 mg PO once daily in patients who are on stable pirtobrutinib therapy. Pirtobrutinib is a CYP3A substrate and weak CYP2C19 inhibitor and mavacamten is a CYP2C19 substrate and moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%. Concomitant use with another weak CYP2C19 inhibitor in CYP2C19 normal and rapid metabolizers increased overall mavacamten exposure by 48%.
Mefloquine: (Moderate) Monitor for an increase in mefloquine-related adverse effects if concomitant use of pirtobrutinib is necessary. Concomitant use may increase mefloquine exposure. Mefloquine is a CYP3A and P-gp substrate and pirtobrutinib is a P-gp and weak CYP3A inhibitor.
Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. If pirtobrutinib is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A and pirtobrutinib is a weak CYP3A inhibitor. Concomitant use with pirtobrutinib can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine.
Metformin; Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with pirtobrutinib is necessary. Repaglinide is a CYP2C8 substrate and pirtobrutinib is a CYP2C8 inhibitor. Concomitant use was observed to increase repaglinide overall exposure by 130%.
Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. If pirtobrutinib is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; pirtobrutinib is a weak CYP2C19 and CYP3A inhibitor. Concomitant use with pirtobrutinib can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone.
Methohexital: (Major) Avoid concurrent use of pirtobrutinib and barbiturates due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Midazolam: (Moderate) Use caution when midazolam is coadministered with pirtobrutinib. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor. Concomitant use was observed to increase midazolam overall exposure by 70%.
Mifepristone: (Major) Avoid concomitant use of pirtobrutinib and mifepristone due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of mifepristone use. Resume the previous dose of pirtobrutinib after mifepristone is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Mitotane: (Major) Avoid concurrent use of pirtobrutinib and mitotane due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with pirtobrutinib is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and pirtobrutinib 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 pirtobrutinib is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and pirtobrutinib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Nafcillin: (Major) Avoid concurrent use of pirtobrutinib and nafcillin 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 nafcillin is a moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Naldemedine: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with pirtobrutinib. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a P-gp substrate; pirtobrutinib is a P-gp inhibitor.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with pirtobrutinib is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP2C8 substrate and pirtobrutinib is a moderate CYP2C8 inhibitor. In vitro, the metabolism of paclitaxel to 6-alpha-hydroxypaclitaxel was inhibited by another inhibitor of CYP2C8.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and pirtobrutinib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and pirtobrutinib is a weak CYP3A and P-gp inhibitor.
Nefazodone: (Major) Avoid concomitant use of pirtobrutinib and nefazodone due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of nefazodone use. Resume the previous dose of pirtobrutinib after nefazodone is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Nelfinavir: (Major) Avoid concomitant use of pirtobrutinib and nelfinavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of nelfinavir use. Resume the previous dose of pirtobrutinib after nelfinavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and nelfinavir is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with pirtobrutinib is necessary. Concurrent use may increase nimodipine exposure. Nimodipine is a CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor.
Nintedanib: (Moderate) Monitor for nintedanib-related adverse reactions if concomitant use of pirtobrutinib is necessary. Concomitant use may increase nintedanib exposure. Nintedanib is a P-gp substrate, and a minor substrate of CYP3A and pirtobrutinib is a dual P-gp and CYP3A inhibitor. Coadministration with another dual P-gp and CYP3A inhibitor increased nintedanib AUC by 60%.
Nirmatrelvir; Ritonavir: (Major) Avoid concomitant use of pirtobrutinib and ritonavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of ritonavir use. Resume the previous dose of pirtobrutinib after ritonavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with pirtobrutinib due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and pirtobrutinib is a CYP3A inhibitor. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concurrent use of pirtobrutinib and rifabutin 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 rifabutin is a moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. If pirtobrutinib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like pirtobrutinib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone.
Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of paclitaxel with pirtobrutinib is necessary due to the risk of increased plasma concentrations of paclitaxel. Paclitaxel is a CYP2C8 substrate and pirtobrutinib is a moderate CYP2C8 inhibitor. In vitro, the metabolism of paclitaxel to 6-alpha-hydroxypaclitaxel was inhibited by another inhibitor of CYP2C8.
Pazopanib: (Major) Avoid coadministration of pazopanib and pirtobrutinib due to the potential for increased pazopanib exposure. Pazopanib is a P-gp and BCRP substrate; pirtobrutinib 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.
Pentobarbital: (Major) Avoid concurrent use of pirtobrutinib and barbiturates due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Pexidartinib: (Major) Avoid concurrent use of pirtobrutinib and pexidartinib 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 pexidartinib is a moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Phenobarbital: (Major) Avoid concurrent use of pirtobrutinib and barbiturates due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concurrent use of pirtobrutinib and barbiturates due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Phenytoin: (Major) Avoid concurrent use of pirtobrutinib and phenytoin due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. The exposure of phenytoin may also be increased. Pirtobrutinib is a CYP3A substrate and CYP2C19 inhibitor; phenytoin is a CYP2C19 substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Pimozide: (Major) Avoid concomitant use of pimozide and pirtobrutinib. Concomitant use may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Pimozide is CYP3A substrate, and pirtobrutinib is a weak CYP3A inhibitor.
Pitavastatin: (Moderate) Monitor for an increase in pitavastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pirtobrutinib is necessary. Concomitant use may increase pitavastatin exposure. Pitavastatin is a P-gp substrate; pirtobrutinib is a P-gp inhibitor.
Posaconazole: (Major) Avoid concomitant use of pirtobrutinib and posaconazole due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. The exposure of posaconazole may also be increased. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of posaconazole use. Resume the previous dose of pirtobrutinib after posaconazole is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and P-gp inhibitor and posaconazole is a P-gp substrate and strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Pralsetinib: (Major) Avoid concomitant use of pirtobrutinib with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a P-gp substrate and pirtobrutinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased the overall exposure of pralsetinib by 81%.
Primidone: (Major) Avoid concurrent use of pirtobrutinib and barbiturates due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and pirtobrutinib 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 pirtobrutinib is a P-gp inhibitor.
Propafenone: (Moderate) Monitor for increased propafenone toxicity if coadministered with pirtobrutinib; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and pirtobrutinib with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; pirtobrutinib is a weak CYP3A inhibitor.
Ranolazine: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with pirtobrutinib is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; pirtobrutinib is a P-gp inhibitor.
Relugolix: (Major) Avoid concomitant use of relugolix and oral pirtobrutinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is necessary, administer pirtobrutinib 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 pirtobrutinib 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 pirtobrutinib is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral pirtobrutinib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is necessary, administer pirtobrutinib 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 pirtobrutinib 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 pirtobrutinib is a P-gp inhibitor.
Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with pirtobrutinib is necessary. Repaglinide is a CYP2C8 substrate and pirtobrutinib is a CYP2C8 inhibitor. Concomitant use was observed to increase repaglinide overall exposure by 130%.
Repotrectinib: (Major) Avoid concurrent use of pirtobrutinib and repotrectinib. Concomitant use may decrease pirtobrutinib exposure and efficacy and increase repotrectinib exposure and the risk for repotrectinib-related adverse effects. While use is not recommended, if concomitant use is necessary, an empiric pirtobrutinib dosage increase is required. If the current pirtobrutinib 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 P-gp inhibitor; repotrectinib is a P-gp substrate and moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Resmetirom: (Major) A resmetirom dosage reduction is required if concomitant use with pirtobrutinib is necessary. For patients with an actual body weight less than 100 kg, reduce the resmetirom dosage to 60 mg once daily. For patients with an actual body weight of 100 kg or more, reduce the resmetirom dosage to 80 mg once daily. Concomitant use may increase resmetirom exposure and the risk for resmetirom-related adverse effects. Resmetirom is a CYP2C8 substrate and pirtobrutinib is a moderate CYP2C8 inhibitor. Concomitant use with another moderate CYP2C8 inhibitor increased resmetirom overall exposure by 1.7-fold.
Ribociclib: (Major) Avoid concomitant use of pirtobrutinib and ribociclib due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of ribociclib use. Resume the previous dose of pirtobrutinib after ribociclib is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Ribociclib; Letrozole: (Major) Avoid concomitant use of pirtobrutinib and ribociclib due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of ribociclib use. Resume the previous dose of pirtobrutinib after ribociclib is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Rifabutin: (Major) Avoid concurrent use of pirtobrutinib and rifabutin 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 rifabutin is a moderate CYP3A inducer. Concomitant use with other moderate CYP3A inducers reduced pirtobrutinib overall exposure by 27% and 49%.
Rifampin: (Major) Avoid concurrent use of pirtobrutinib and rifampin due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use reduced pirtobrutinib overall exposure by 71%.
Rifapentine: (Major) Avoid concurrent use of pirtobrutinib and rifapentine due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and rifapentine is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with pirtobrutinib 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 pirtobrutinib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with pirtobrutinib; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and pirtobrutinib is a P-gp inhibitor.
Ritonavir: (Major) Avoid concomitant use of pirtobrutinib and ritonavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of ritonavir use. Resume the previous dose of pirtobrutinib after ritonavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Rosiglitazone: (Moderate) Monitor for an increase in rosiglitazone-related adverse effects during concomitant use with pirtobrutinib; adjust the dose of rosiglitazone based on clinical response. Coadministration may increase the exposure of rosiglitazone. Rosiglitazone is a CYP2C8 substrate and pirtobrutinib is a CYP2C8 inhibitor.
Rosuvastatin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with pirtobrutinib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and pirtobrutinib is a BCRP inhibitor. Concomitant use was observed to increase rosuvastatin overall exposure by 140%.
Rosuvastatin; Ezetimibe: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with pirtobrutinib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and pirtobrutinib is a BCRP inhibitor. Concomitant use was observed to increase rosuvastatin overall exposure by 140%.
Saquinavir: (Major) Avoid concomitant use of pirtobrutinib and saquinavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. The exposure of saquinavir may also be increased. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of saquinavir use. Resume the previous dose of pirtobrutinib after saquinavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and P-gp inhibitor and saquinavir is a P-gp substrate and strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Secobarbital: (Major) Avoid concurrent use of pirtobrutinib and barbiturates due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Selexipag: (Major) Reduce the selexipag dose to once daily if coadministered with pirtobrutinib. Concomitant use may increase selexipag exposure and the risk of adverse effects. Selexipag is a CYP2C8 substrate and pirtobrutinib is a moderate CYP2C8 inhibitor. Coadministration with another moderate CYP2C8 inhibitor increased exposure to the active selexipag metabolite by approximately 2.7-fold.
Silodosin: (Major) Avoid coadministration of silodosin and pirtobrutinib due to the potential for increased silodosin exposure. In vitro data indicate that silodosin is a P-gp substrate; pirtobrutinib is a P-gp inhibitor.
Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pirtobrutinib is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; pirtobrutinib is a P-gp inhibitor.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of pirtobrutinib. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and pirtobrutinib is a weak CYP3A and P-gp inhibitor.
Sotorasib: (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%.
St. John's Wort, Hypericum perforatum: (Major) Avoid concurrent use of pirtobrutinib and St. John's wort due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if pirtobrutinib must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of pirtobrutinib is necessary. If pirtobrutinib is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A substrate, and coadministration with a weak CYP3A inhibitor like pirtobrutinib can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with pirtobrutinib is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; pirtobrutinib is a weak CYP3A inhibitor.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of pirtobrutinib is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a P-gp and BCRP substrate; pirtobrutinib is a P-gp and BCRP inhibitor.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with pirtobrutinib is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and pirtobrutinib is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with pirtobrutinib 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 and pirtobrutinib is a P-gp and BCRP inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with pirtobrutinib 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 and pirtobrutinib is a P-gp and BCRP inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with pirtobrutinib 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 pirtobrutinib is a P-gp and BCRP inhibitor.
Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with pirtobrutinib as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and pirtobrutinib is a P-gp inhibitor.
Tipranavir: (Major) Avoid concomitant use of pirtobrutinib and tipranavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. The exposure of tipranavir may also be increased. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of tipranavir use. Resume the previous dose of pirtobrutinib after tipranavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and P-gp inhibitor and tipranavir is a P-gp substrate and strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Topotecan: (Major) Avoid coadministration of pirtobrutinib with oral topotecan due to increased topotecan exposure; pirtobrutinib may be administered with intravenous topotecan. Coadministration increases the risk of topotecan-related adverse reactions. Oral topotecan is a P-gp and BCRP substrate and pirtobrutinib is a P-gp and BCRP inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Tovorafenib: (Major) Avoid concomitant use of tovorafenib and pirtobrutinib due to the risk for increased tovorafenib exposure which may increase the risk for tovorafenib-related adverse effects. Tovorafenib is a CYP2C8 substrate and pirtobrutinib is a moderate CYP2C8 inhibitor.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with pirtobrutinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of pirtobrutinib, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with pirtobrutinib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of pirtobrutinib, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with pirtobrutinib. Coadministration may increase the exposure of triazolam. Triazolam is a sensitive CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor.
Tucatinib: (Major) Avoid concomitant use of pirtobrutinib and tucatinib due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. The exposure of tucatinib may also be increased. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of tucatinib use. Resume the previous dose of pirtobrutinib after tucatinib is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and moderate CYP2C8 inhibitor and tucatinib is a CYP2C8 substrate and strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with pirtobrutinib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A, P-gp, and BCRP substrate; pirtobrutinib is a weak CYP3A, P-gp, and BCRP inhibitor.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with pirtobrutinib due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of pirtobrutinib. Venetoclax is a P-gp substrate; pirtobrutinib is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Vincristine Liposomal: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of pirtobrutinib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and pirtobrutinib is a P-gp inhibitor.
Vincristine: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of pirtobrutinib is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and pirtobrutinib is a P-gp inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with pirtobrutinib is necessary. Vinorelbine is a CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of pirtobrutinib and clarithromycin due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of clarithromycin use. Resume the previous dose of pirtobrutinib after clarithromycin is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Voriconazole: (Major) Avoid concomitant use of pirtobrutinib and voriconazole due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of voriconazole use. Resume the previous dose of pirtobrutinib after voriconazole is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with pirtobrutinib is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and pirtobrutinib is a weak CYP3A inhibitor. 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.
Pirtobrutinib is a Bruton tyrosine kinase (BTK) inhibitor. BTK is a signaling molecule in the B-cell antigen receptor (BCR) and cytokine receptor pathways. Signaling from BCR regulates B-cell proliferation, trafficking, chemotaxis, and adhesion. Pirtobrutinib inhibits BTK enzymatic activity in wild-type BTK and BTK with C481 mutations. It inhibited BTK-mediated B-cell CD69 expression and malignant B-cell proliferation in non-clinical studies. Additionally, pirtobrutinib has demonstrated dose-dependent anti-tumor activity in mouse xenograft models. Pirtobrutinib is a highly selective, reversible (non-covalent), third generation BTK inhibitor. Unlike other BTK inhibitors (i.e., ibrutinib, acalabrutinib, and zanubrutinib), it does not rely on binding to the cysteine 481 amino acid within the active site of BTK. The development of C481 mutations appear to be a mechanism of resistance to covalently binding BTK inhibitors.
Pirtobrutinib is administered orally. It is 96% protein bound, with a mean blood-to-plasma ratio of 0.79. The mean apparent central volume of distribution of pirtobrutinib is 34.1 L. The effective half-life of pirtobrutinib is approximately 19 hours. The mean (CV%) apparent clearance is 2.05 L/hour (37.2%). Pirtobrutinib is metabolized primarily via CYP3A4 and direct glucuronidation via UGT1A8 and UGT1A9 in vitro. After a single radiolabeled dose of 200 mg in healthy subjects, 37% of the dose was recovered in feces (18% unchanged) and 57% in urine (10% unchanged).
Pirtobrutinib trough concentrations exceeded the BTK IC96 at the recommended dosage of 200 mg once daily; BTK occupancy is maintained throughout the dosing interval.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A, P-gp, CYP2C8, BCRP, and CYP2C19
Pirtobrutinib is a substrate of CYP3A, an inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), a moderate inhibitor of CYP2C8, and a weak inhibitor of CYP2C19 and CYP3A. In vitro, pirtobrutinib is a substrate and inhibitor P-gp and BCRP; it also inhibits CYP2C8, CYP2C9, CYP3A, CYP1A2, CYP2B6, CYP2C19, and CYP2D6 and induces CYP3A4, CYP3A5, CYP2B6, and CYP2C19.
-Route-Specific Pharmacokinetics
Oral Route
After oral administration of 200 mg once daily, steady state was achieved within 5 days and the mean (CV%) accumulation ratio was 1.63 (26.7%) based on AUC. The geometric mean (CV%) steady-state AUC value was 90,300 nanograms (ng) x hours/mL (40%) and the Cmax was 6,380 ng/mL (26%). The absolute bioavailability of pirtobrutinib after a single oral 200 mg dose is 85.5% (range, 75.9% to 90.9%). The median time to reach peak plasma concentration (Tmax) is approximately 2 (range, 0.833 to 4.15) hours.
Effects of food: Administration with a high-fat, high-calorie meal (approximately 800 to 1,000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) did not have a clinically significant effect on the pharmacokinetic parameters of pirtobrutinib compared with the fasted state in healthy subjects. Taking pirtobrutinib with a high-fat meal decreased the Cmax by 23% and delayed the Tmax by 1 hour; the AUC value was not changed.
-Special Populations
Hepatic Impairment
Hepatic impairment did not have a clinically significant effect on the pharmacokinetic parameters of pirtobrutinib for mild (total bilirubin level at the upper limit of normal (ULN) or less and AST level more than the ULN, or total bilirubin level more than 1 to 1.5 times the ULN and any AST level), moderate (total bilirubin level more than 1.5 to 3 times the ULN and any AST level), or severe (total bilirubin level more than 3 times the ULN and any AST level) hepatic impairment.
Renal Impairment
Mild (estimated glomerular filtration rate [eGFR], 60 to 89 mL/min) or moderate (eGFR, 30 to 59 mL/min) renal impairment did not have a clinically significant effect on the pharmacokinetic (PK) parameters of pirtobrutinib. Following a single 200 mg oral dose of pirtobrutinib, the AUC value was increased by 62% in subjects with severe renal impairment (eGFR, 15 to 29 mL/min) compared with subjects who had normal renal function. The effect of renal impairment requiring dialysis on the PK parameters of pirtobrutinib is unknown.
Geriatric
Age (range, 22 to 95 years) did not have a clinically significant effect on the pharmacokinetic parameters of pirtobrutinib.
Gender Differences
Gender did not have a clinically significant effect on the pharmacokinetics of pirtobrutinib.
Ethnic Differences
Race (i.e., White patients, Asian patients) did not have a clinically significant effect on the pharmacokinetic parameters of pirtobrutinib.
Obesity
Body weight (35.7 to 152 kg) did not have a clinically significant effect on the pharmacokinetic parameters of pirtobrutinib.