PIRTOBRUTINIB Drug Interactions: What You Need to Know

INTERACTIONS Strong CYP3A Inhibitors: Avoid concomitant use. If concomitant use is unavoidable, reduce the JAYPIRCA dose. ( 2.4 , 7.1 ) Strong or Moderate CYP3A Inducers: Avoid concomitant use. If concomitant use of moderate CYP3A inducers is unavoidable, increase the JAYPIRCA dose. ( 2.5 , 7.1 ) Sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP Substrates: For substrates where minimal concentration changes may increase the risk of adverse reactions, follow recommendations for co-administration with CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP inhibitors provided in their approved product labeling. ( 7.2 )

7.1 Effect of Other Drugs on JAYPIRCA Strong CYP3A Inhibitors Pirtobrutinib is a CYP3A substrate. Concomitant use of JAYPIRCA with a strong CYP3A inhibitor increased pirtobrutinib systemic exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> , which may increase the risk of JAYPIRCA adverse reactions. Avoid concomitant use of strong CYP3A inhibitors during treatment with JAYPIRCA. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the JAYPIRCA dosage <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span> . Strong or Moderate CYP3A Inducers Concomitant use of JAYPIRCA with a strong or moderate CYP3A inducer decreased pirtobrutinib systemic exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> , which may reduce JAYPIRCA efficacy. Avoid concomitant use of JAYPIRCA with strong or moderate CYP3A inducers. If concomitant use of moderate CYP3A inducers is unavoidable, increase the JAYPIRCA dosage <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.5 )]</span> .

7.2 Effect of JAYPIRCA on Other Drugs Sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP Substrates JAYPIRCA is a P-gp inhibitor, a moderate CYP2C8 and BCRP inhibitor, and a weak CYP2C19 and CYP3A inhibitor. Concomitant use of JAYPIRCA with sensitive P-gp, CYP2C8, BCRP, CYP2C19, or CYP3A substrates increased their plasma concentrations <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>, which may increase the risk of adverse reactions related to these substrates for drugs which are sensitive to minimal concentration changes. Follow recommendations for sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP substrates provided in their approved product labeling.

None. None ( 4 ).

AND PRECAUTIONS Infections: Monitor for signs and symptoms of infection, evaluate promptly, and treat. ( 5.1 ) Hemorrhage: Monitor for bleeding and manage appropriately. ( 5.2 ) Cytopenias: Monitor complete blood counts during treatment. ( 5.3 )

Cardiac

Arrythmias: Monitor for symptoms of arrhythmias and manage appropriately. ( 5.4 )

Second Primary

Malignancies: Other malignancies have developed, including skin cancers and other carcinomas. Monitor and advise patients to use sun protection. ( 5.5 ) Hepatotoxicity, Including Drug-Induced Liver Injury: Monitor hepatic function throughout treatment. ( 5.6 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 )

5.1 Infections Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients treated with JAYPIRCA. Across clinical trials, Grade 3 or higher infections occurred in 25% of 704 patients, most commonly pneumonia (20%), with fatal infections occurring in 5% of patients. Sepsis occurred in 6% of patients and febrile neutropenia in 3.8%. In patients with CLL/SLL, Grade 3 or higher infections occurred in 32% of patients, with fatal infections occurring in 8%. Opportunistic infections after treatment with JAYPIRCA have included, but are not limited to, Pneumocystis jirovecii pneumonia and fungal infection <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Consider prophylaxis, including vaccinations and antimicrobial prophylaxis, in patients who are at increased risk for infections, including opportunistic infections. Monitor patients for signs and symptoms of infection, evaluate promptly, and treat appropriately. Based on severity, reduce dose, temporarily withhold, or permanently discontinue JAYPIRCA <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .

5.2 Hemorrhage Fatal and serious hemorrhage has occurred with JAYPIRCA. Major hemorrhage (defined as Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 2.6% of 704 patients treated with JAYPIRCA, including gastrointestinal hemorrhage; fatal hemorrhage occurred in 0.3% of patients. Bleeding of any grade, excluding bruising and petechiae, occurred in 16% of patients <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Major hemorrhage occurred in 0.6% of patients taking JAYPIRCA without antithrombotic agents and 2.0% of patients taking JAYPIRCA with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with JAYPIRCA. Monitor patients for signs of bleeding. Based on severity of bleeding, reduce dose, temporarily withhold, or permanently discontinue JAYPIRCA <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> . Consider the benefit-risk of withholding JAYPIRCA for 3 to 7 days pre- and post-surgery depending upon the type of surgery and risk of bleeding.

5.3 Cytopenias JAYPIRCA can cause cytopenias, including neutropenia, thrombocytopenia, and anemia. Across clinical trials, Grade 3 or 4 cytopenias, including decreased neutrophils (27%), decreased platelets (13%), and decreased hemoglobin (11%) developed in patients treated with JAYPIRCA.

Grade

4 decreased neutrophils developed in 15% of patients and Grade 4 decreased platelets developed in 6% of patients [see Adverse Reactions ( 6.1 )] . Monitor complete blood counts regularly during treatment. Based on severity, reduce dose, temporarily withhold, or permanently discontinue JAYPIRCA [see Dosage and Administration ( 2.2 )].

5.4 Cardiac Arrhythmias Cardiac arrhythmias, including atrial fibrillation and atrial flutter, were reported in recipients of JAYPIRCA. Atrial fibrillation or flutter were reported in 3.4% of patients, with Grade 3 or 4 atrial fibrillation or flutter reported in 1.6% of 704 patients across clinical trials <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Other serious cardiac arrhythmias such as supraventricular tachycardia and cardiac arrest occurred in 0.4% of patients. Patients with cardiac 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. Based on severity, reduce dose, temporarily withhold, or permanently discontinue JAYPIRCA <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .

5.5 Second Primary Malignancies Second primary malignancies, including non-skin carcinomas, developed in 9% of 704 patients treated with JAYPIRCA monotherapy across clinical trials. The most frequent malignancy was non-melanoma skin cancer, reported in 4.4% of 704 patients. Other second primary malignancies included solid tumors (including genitourinary and breast cancers) and melanoma. Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

5.6 Hepatotoxicity, Including Drug-Induced Liver Injury Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including JAYPIRCA. Evaluate bilirubin and transaminases at baseline and throughout treatment with JAYPIRCA. For patients who develop abnormal liver tests after JAYPIRCA, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold JAYPIRCA. Upon confirmation of DILI, discontinue JAYPIRCA.

5.7 Embryo-Fetal Toxicity Based on findings in animals, JAYPIRCA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of pirtobrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity including embryo-fetal mortality and malformations at maternal exposures (AUC) approximately 3-times the recommended dose of 200 mg once daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with JAYPIRCA and for one week after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span>.