ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Infections [see Warnings and Precautions (5.1)] Hemorrhage [see Warnings and Precautions (5.2)] Cytopenias [see Warnings and Precautions (5.3)] Atrial Fibrillation and Atrial Flutter [see Warnings and Precautions (5.4)] Second Primary Malignancies [see Warnings and Precautions (5.5)] Infections [see Warnings and Precautions (5.1)] Hemorrhage [see Warnings and Precautions (5.2)] Cytopenias [see Warnings and Precautions (5.3)] Atrial Fibrillation and Atrial Flutter [see Warnings and Precautions (5.4)] Second Primary Malignancies [see Warnings and Precautions (5.5)] Most common adverse reactions (>= 15%) in patients with MCL are fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade or laboratory abnormalities (>= 10%) are neutrophil count decreased, lymphocyte count decreased, and platelet count decreased. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be compared to rates in the clinical trials of another drug and may not reflect the rates observed in the general patient population.The data in the WARNINGS AND PRECAUTIONS reflect exposure to JAYPIRCA as single-agent, administered at 200 mg once daily in 583 patients with hematologic malignancies in the BRUIN study. Among these 583 patients, the median duration of exposure was 7.5 months, 56% were exposed for at least months and 29% were exposed for at least one year.In this pooled safety population, the most common (>= 20%) adverse reactions, including laboratory abnormalities, were decreased neutrophil count (41%), decreased hemoglobin (37%), decreased platelet count (27%), fatigue (27%), musculoskeletal pain (26%), decreased lymphocyte count (24%), bruising (20%), and diarrhea (20%).. Mantle Cell Lymphoma. BRUINThe safety of JAYPIRCA was evaluated in the BRUIN trial in patients with MCL who received prior BTK inhibitor [see Clinical Studies (14.1 )]. The trial required platelet count >= 50 109/L, absolute neutrophil count >= 0.75 109/L, hepatic transaminases <= 2.5 times upper limit of normal (ULN), and an ECOG performance status of to 2. The trial excluded patients with active central nervous system (CNS) involvement by lymphoma, significant cardiovascular disease, major bleeding or grade >= arrhythmia with prior BTK inhibitor, prolonged QTc interval, or need for strong CYP3A inhibitor or inducer or strong P-gp inhibitor.Patients received JAYPIRCA 200 mg orally once daily until disease progression or unacceptable toxicity (n 128); 36% were exposed for months or longer and 10% were exposed for at least one year. The median number of prior therapies was (range: 1-9). The median age was 71 years (range: 46 to 88 years) and 80% of patients were male.Serious adverse reactions occurred in 38% of patients who received JAYPIRCA. Serious adverse reactions that occurred in >= 2% of patients were pneumonia (14%), COVID-19 (4.7%), musculoskeletal pain (3.9%), hemorrhage (2.3%), pleural effusion (2.3%), and sepsis (2.3%). Fatal adverse reactions within 28 days of the last dose of JAYPIRCA occurred in 7% of patients, most commonly due to infections (4.7%) including COVID-19 (3.1% of all patients).Adverse reactions led to dosage reductions in 4.7%, treatment interruption in 32%, and permanent discontinuation of JAYPIRCA in 9%. Adverse reactions that resulted in dosage modification in 5% of patients included pneumonia and neutropenia. Adverse reactions which resulted in permanent discontinuation of JAYPIRCA in 1% of patients included pneumonia.The most common adverse reactions (>= 15%), excluding laboratory terms, were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising.Table summarizes select adverse reactions in BRUIN.Table 2: Adverse Reactions (>= 10%) in Patients with MCL Who Received JAYPIRCAJAYPIRCA200 mg once dailyN 128a Each term listed includes other related terms.b includes fatality from COVID-19 pneumoniac includes fatality from hemorrhageAdverse ReactionsaAll Grades (%)Grade 3-4 (%)General DisordersFatigue291.6Edema180.8Fever13-Musculoskeletal and Connective Tissue DisordersMusculoskeletal pain273.9Arthritis or arthralgia120.8Gastrointestinal DisordersDiarrhea19-Constipation13-Abdominal pain110.8Nausea11-Respiratory, thoracic, and mediastinal disordersDyspnea172.3Cough14-InjuryBruising16-InfectionsPneumonia16 14Upper respiratory tract infections100.8Nervous system disordersPeripheral neuropathy140.8Dizziness10-Skin and subcutaneous disordersRash14-Vascular disordersHemorrhage11 3.1Clinically relevant adverse reactions in 10% include vision changes, memory changes, headache, urinary tract infection, herpesvirus infection, and tumor lysis syndrome.Table summarizes laboratory abnormalities in BRUIN.Table 3: Select Laboratory Abnormalities (>= 10%) That Worsened from Baseline in Patients with MCL Who Received JAYPIRCAa The denominator used to calculate the rate varied from 90 to 127 based on the number of patients with baseline value and at least one post-treatment value.Laboratory AbnormalityJAYPIRCAa200 mg once dailyAll Grades (%)Grade or (%)HematologyHemoglobin decreased429Platelet count decreased3914Neutrophil count decreased3616Lymphocyte count decreased3215ChemistryCreatinine increased301.6Calcium decreased191.6AST increased171.6Potassium decreased131.6Sodium decreased13-Lipase increased124.4Alkaline phosphatase increased11-ALT increased111.6Potassium increased110.8Grade laboratory abnormalities in 5% of patients included neutrophils decreased (10%), platelets decreased (7%), and lymphocytes decreased (6%).Lymphocytosis: Upon initiation of JAYPIRCA, temporary increase in lymphocyte counts (defined as absolute lymphocyte count increased >= 50% from baseline and post-baseline value >= 5,000/uL) occurred in 34% of MCL patients in BRUIN. The median time to onset of lymphocytosis was 1.1 weeks, with 75% of cases occurring within 2.1 weeks, and the median duration was 11 weeks.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, mutagenesis, impairment of fertility. Carcinogenicity studies have not been conducted with pirtobrutinib.Pirtobrutinib was not mutagenic in bacterial mutagenicity (Ames) assay. Pirtobrutinib was aneugenic in in vitro micronucleus assays using human peripheral blood lymphocytes. Pirtobrutinib was not genotoxic in an in vivo rat bone marrow micronucleus assay at doses up to 2000 mg/kg.Studies to assess the effects of pirtobrutinib on fertility have not been conducted. In repeat-dose toxicity studies of up to 3-months duration conducted with pirtobrutinib in rats and dogs, no effects on male or female reproductive organs were identified.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of action. Pirtobrutinib is small molecule, noncovalent inhibitor of BTK. BTK is signaling protein of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Pirtobrutinib binds to wild type BTK and BTK harboring C481 mutations, leading to inhibition of BTK kinase activity. In nonclinical studies, pirtobrutinib inhibited BTK-mediated B-cell CD69 expression and inhibited malignant B-cell proliferation. Pirtobrutinib showed dose-dependent anti-tumor activities in BTK wild type and BTK C481S mutant mouse xenograft models.. 12.2 Pharmacodynamics. At the recommended dosage of 200 mg once daily, pirtobrutinib trough concentrations exceeded the BTK IC96. BTK occupancy is maintained throughout the dosing interval, regardless of the intrinsic rate of BTK turnover.. Cardiac ElectrophysiologyThe effect of single 900 mg dose of pirtobrutinib (equivalent to approximately times higher than the concentrations achieved at steady state at the recommended dosage of 200 mg once daily) on the QTc interval was evaluated in placebo-controlled and positive-controlled study in 30 healthy subjects. Pirtobrutinib had no clinically meaningful effect on the change in QTcF interval (i.e., 10 ms) and there was no relationship between pirtobrutinib exposure and change in QTc interval.. 12.3 Pharmacokinetics. The pharmacokinetics of pirtobrutinib were characterized in healthy subjects and in patients with cancer. Pirtobrutinib exposure (AUC) and Cmax increases proportionally following single oral doses ranging from 300 mg to 800 mg (1.5 to times the approved recommended dosage) and once daily doses ranging from 25 300 mg (0.125 to 1.5 times the recommended dosage). Steady state was achieved within days of once daily dosing, and the mean (CV%) accumulation ratio was 1.63 (26.7%) based on AUC after administration of 200 mg dosages.Following administration of the recommended dosage, the geometric mean (CV%) steady-state AUC and Cmax of pirtobrutinib were 91300 hng/mL (41%) and 6460 ng/mL (26%), respectively. The geometric mean (CV%) AUC0-24 and Cmax of pirtobrutinib on Cycle Day were 81800 hng/mL (66.6%) and 3670 ng/mL (89.5%), respectively.. AbsorptionThe absolute bioavailability of pirtobrutinib after single oral 200 mg dose is 85.5% (range 75.9% to 90.9%). The median time (range) to reach peak plasma concentration (tmax) is approximately hours (0.833 to 4.15 hours).. Effect of FoodNo clinically significant differences in the pharmacokinetics of pirtobrutinib were observed following administration of high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) to healthy subjects. high-fat meal decreased the Cmax of pirtobrutinib by 23% and delayed tmax by hour. There was no effect on pirtobrutinib AUC.. DistributionThe mean apparent central volume of distribution of pirtobrutinib is 32.8 L. Human protein binding of pirtobrutinib is 96% and is independent of concentration in vitro. Mean blood-to-plasma ratio is 0.79.. EliminationThe effective half-life of pirtobrutinib is approximately 19 hours and the mean (CV%) apparent clearance is 2.02 L/h (37.9%).. MetabolismPirtobrutinib is primarily metabolized by CYP3A4 and direct glucuronidation by UGT1A8 and UGT1A9, in vitro.. ExcretionFollowing single radiolabeled dose of pirtobrutinib 200 mg to healthy subjects, 37% of the dose was recovered in feces (18% unchanged) and 57% in urine (10% unchanged).. Specific PopulationsThere were no clinically significant differences in the pharmacokinetics of pirtobrutinib based on age (range 27 95 years), sex, race/ethnicity (White 86%, Asian 7%), body weight (range 35.7 152.5 kg), mild (total bilirubin <= upper limit of normal (ULN) and aspartate aminotransferase (AST) ULN or total bilirubin 1 to 1.5 ULN and any AST), moderate (total bilirubin 1.5 to x ULN and any AST), or severe (total bilirubin 3 ULN and any AST) hepatic impairment. The effect of other races/ethnicities on the pharmacokinetics of pirtobrutinib is unknown.. Patients with Renal ImpairmentFollowing single 200 mg oral dose, the AUC of pirtobrutinib in subjects with severe renal impairment (eGFR 15-29 mL/min) increased by 62% and mean unbound AUC increased by 68% compared to healthy subjects with normal renal function. There were no clinically significant differences in the pharmacokinetics of pirtobrutinib in subjects with mild (eGFR 60-89 mL/min) or moderate renal impairment (eGFR 30-59 mL/min). The effect of renal impairment requiring dialysis on the pharmacokinetics of pirtobrutinib is unknown.. Drug Interaction Studies. Clinical Studies and Model-Informed ApproachesStrong CYP3A Inhibitors: Co-administration of single 200 mg dose of pirtobrutinib with itraconazole (strong CYP3A inhibitor) increased AUC of pirtobrutinib by 49%.Moderate CYP3A Inhibitors: Verapamil and diltiazem (moderate CYP3A inhibitors) are predicted to increase the AUC of pirtobrutinib by 30% and 20%, respectively.Strong CYP3A inducers: Coadministration of single 200 mg dose of pirtobrutinib with rifampin (strong CYP3A inducer) decreased the AUC of pirtobrutinib by 71%.Moderate CYP3A Inducers: Efavirenz and bosentan (moderate CYP3A inducers) are predicted to decrease the AUC of pirtobrutinib by 49% and 27%, respectively.Gastric Reducing Agents: No clinically significant differences in pirtobrutinib pharmacokinetics were observed when co-administered with omeprazole (a proton pump inhibitor).P-glycoprotein (P-gp) inhibitors: No clinically significant differences in pirtobrutinib pharmacokinetics were observed when co-administered with itraconazole (P-gp inhibitor).CYP3A Substrates: Pirtobrutinib increased the AUC and Cmax of orally administered midazolam (sensitive CYP3A substrate) by 70% and 58%, respectively. Pirtobrutinib did not have clinically meaningful effect on the exposure of intravenously administered midazolam.CYP2C8 Substrates: Pirtobrutinib increased the AUC and Cmax of repaglinide (sensitive CYP2C8 substrate) by 130% and 98%, respectively.CYP2C19 Substrates: Pirtobrutinib increased the AUC and Cmax of omeprazole (sensitive CYP2C19 substrate) by 56% and 49%, respectively.P-gp Substrates: single 200 mg dose of pirtobrutinib increased the AUC and Cmax of digoxin (sensitive P-gp substrate) by 17% and 51%, respectively. Multiple doses of pirtobrutinib (200 mg daily) further increased the AUC and Cmax of digoxin (sensitive P-gp substrate) up to 35% and 55%, respectively.BCRP Substrates: Multiple doses of pirtobrutinib (200 mg daily) increased the AUC and Cmax of rosuvastatin (sensitive BCRP substrate) by 140% and 146%, respectively.CYP1A2 and CYP2C9 Substrates: Pirtobrutinib did not have clinically meaningful effect on the exposures of caffeine (sensitive CYP1A2 substrate) or S-warfarin (moderate sensitive CYP2C9 substrate).. In Vitro StudiesCytochrome P450 (CYP) Enzymes: Pirtobrutinib inhibits CYP2C8, CYP2C9, CYP3A, CYP1A2, CYP2B6, CYP2C19, and CYP2D6. Pirtobrutinib induces CYP3A4, CYP3A5, CYP2B6, and CYP2C19.Transporter Systems: Pirtobrutinib inhibits P-gp and BCRP, but not OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K. Pirtobrutinib is not substrate of the hepatic transporters. Pirtobrutinib is substrate of P-gp and BCRP, but not OCT1, OATP1B1, OATP1B3, or BSEP.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Mantle Cell Lymphoma. The efficacy of JAYPIRCA in patients with MCL was evaluated in BRUIN [NCT03740529], an open-label, international, single-arm study of JAYPIRCA as monotherapy. Efficacy was based on 120 patients with MCL treated with JAYPIRCA who were previously treated with BTK inhibitor. JAYPIRCA was given orally at dose of 200 mg once daily and was continued until disease progression or unacceptable toxicity. Patients with active central nervous system lymphoma or allogeneic hematopoietic stem cell transplantation (HSCT) or CAR-T cell therapy within 60 days were excluded.The median age was 71 years (range: 46 to 88 years); 79% were male; 78% were White, 14% Asian, 1.7% Black or African American. Seventy-eight percent of patients had the classic/leukemic variant of MCL, 12% had pleomorphic MCL, and 11% had blastoid MCL. The simplified Mantle Cell Lymphoma International Prognostic Index (sMIPI) score was low in 15%, intermediate in 59%, and high in 26% of patients. Patients received median number of prior lines of therapy (range: to 9) with 93% having received or more prior lines. All received or more prior lines of therapy containing BTK inhibitor; other prior therapies included chemoimmunotherapy in 88%, HSCT in 20%, lenalidomide in 18%, and CAR-T therapy in 9%. The most common prior BTK inhibitors received were ibrutinib (67%), acalabrutinib (30%), and zanubrutinib (8%). Patients may have received more than one prior BTK inhibitor; 83% of patients discontinued the last BTK inhibitor for refractory or progressive disease, 10% discontinued for toxicity, and 5% discontinued for other reasons.Efficacy was based on overall response rate (ORR) and duration of response (DOR), as assessed by an independent review committee (IRC) using 2014 Lugano criteria. Efficacy results are shown in Table 4. Additionally, the Kaplan-Meier estimate for the DOR rate at months was 65.3% (95% CI: 49.8, 77.1).Table 4: Efficacy Results per IRC in Patients with MCL Previously Treated with BTK InhibitorCI, confidence interval; CR, complete response; DOR, duration of response; PR, partial response; NE, not estimable.a PET-CT scans were utilized in response assessments (in 41% of patients), with the remainder being assessed by CT scans only.b ORR using CT scan-based assessments in all patients was 48% (95% CI: 38, 57) and CR rate was 13%.c Based on Kaplan-Meier estimation. Estimated median follow-up was 7.3 months.OutcomeJAYPIRCA 200 mg once daily(N 120)Overall Response Ratea,b ORR, n60 (50%) (95% CI, %)41, 59CR, n15 (13%)PR, n45 (38%)Time to ResponseMedian (range), months1.8 (0.8, 4.2)Duration of Responsec Number censored, n36 Median DOR, months (95% CI)8.3 (5.7, NE).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be compared to rates in the clinical trials of another drug and may not reflect the rates observed in the general patient population.The data in the WARNINGS AND PRECAUTIONS reflect exposure to JAYPIRCA as single-agent, administered at 200 mg once daily in 583 patients with hematologic malignancies in the BRUIN study. Among these 583 patients, the median duration of exposure was 7.5 months, 56% were exposed for at least months and 29% were exposed for at least one year.In this pooled safety population, the most common (>= 20%) adverse reactions, including laboratory abnormalities, were decreased neutrophil count (41%), decreased hemoglobin (37%), decreased platelet count (27%), fatigue (27%), musculoskeletal pain (26%), decreased lymphocyte count (24%), bruising (20%), and diarrhea (20%).. Mantle Cell Lymphoma. BRUINThe safety of JAYPIRCA was evaluated in the BRUIN trial in patients with MCL who received prior BTK inhibitor [see Clinical Studies (14.1 )]. The trial required platelet count >= 50 109/L, absolute neutrophil count >= 0.75 109/L, hepatic transaminases <= 2.5 times upper limit of normal (ULN), and an ECOG performance status of to 2. The trial excluded patients with active central nervous system (CNS) involvement by lymphoma, significant cardiovascular disease, major bleeding or grade >= arrhythmia with prior BTK inhibitor, prolonged QTc interval, or need for strong CYP3A inhibitor or inducer or strong P-gp inhibitor.Patients received JAYPIRCA 200 mg orally once daily until disease progression or unacceptable toxicity (n 128); 36% were exposed for months or longer and 10% were exposed for at least one year. The median number of prior therapies was (range: 1-9). The median age was 71 years (range: 46 to 88 years) and 80% of patients were male.Serious adverse reactions occurred in 38% of patients who received JAYPIRCA. Serious adverse reactions that occurred in >= 2% of patients were pneumonia (14%), COVID-19 (4.7%), musculoskeletal pain (3.9%), hemorrhage (2.3%), pleural effusion (2.3%), and sepsis (2.3%). Fatal adverse reactions within 28 days of the last dose of JAYPIRCA occurred in 7% of patients, most commonly due to infections (4.7%) including COVID-19 (3.1% of all patients).Adverse reactions led to dosage reductions in 4.7%, treatment interruption in 32%, and permanent discontinuation of JAYPIRCA in 9%. Adverse reactions that resulted in dosage modification in 5% of patients included pneumonia and neutropenia. Adverse reactions which resulted in permanent discontinuation of JAYPIRCA in 1% of patients included pneumonia.The most common adverse reactions (>= 15%), excluding laboratory terms, were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising.Table summarizes select adverse reactions in BRUIN.Table 2: Adverse Reactions (>= 10%) in Patients with MCL Who Received JAYPIRCAJAYPIRCA200 mg once dailyN 128a Each term listed includes other related terms.b includes fatality from COVID-19 pneumoniac includes fatality from hemorrhageAdverse ReactionsaAll Grades (%)Grade 3-4 (%)General DisordersFatigue291.6Edema180.8Fever13-Musculoskeletal and Connective Tissue DisordersMusculoskeletal pain273.9Arthritis or arthralgia120.8Gastrointestinal DisordersDiarrhea19-Constipation13-Abdominal pain110.8Nausea11-Respiratory, thoracic, and mediastinal disordersDyspnea172.3Cough14-InjuryBruising16-InfectionsPneumonia16 14Upper respiratory tract infections100.8Nervous system disordersPeripheral neuropathy140.8Dizziness10-Skin and subcutaneous disordersRash14-Vascular disordersHemorrhage11 3.1Clinically relevant adverse reactions in 10% include vision changes, memory changes, headache, urinary tract infection, herpesvirus infection, and tumor lysis syndrome.Table summarizes laboratory abnormalities in BRUIN.Table 3: Select Laboratory Abnormalities (>= 10%) That Worsened from Baseline in Patients with MCL Who Received JAYPIRCAa The denominator used to calculate the rate varied from 90 to 127 based on the number of patients with baseline value and at least one post-treatment value.Laboratory AbnormalityJAYPIRCAa200 mg once dailyAll Grades (%)Grade or (%)HematologyHemoglobin decreased429Platelet count decreased3914Neutrophil count decreased3616Lymphocyte count decreased3215ChemistryCreatinine increased301.6Calcium decreased191.6AST increased171.6Potassium decreased131.6Sodium decreased13-Lipase increased124.4Alkaline phosphatase increased11-ALT increased111.6Potassium increased110.8Grade laboratory abnormalities in 5% of patients included neutrophils decreased (10%), platelets decreased (7%), and lymphocytes decreased (6%).Lymphocytosis: Upon initiation of JAYPIRCA, temporary increase in lymphocyte counts (defined as absolute lymphocyte count increased >= 50% from baseline and post-baseline value >= 5,000/uL) occurred in 34% of MCL patients in BRUIN. The median time to onset of lymphocytosis was 1.1 weeks, with 75% of cases occurring within 2.1 weeks, and the median duration was 11 weeks.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Pirtobrutinib is kinase inhibitor. It is an orally available, small molecule ATP-competitive inhibitor of BTK. The active pharmaceutical ingredient is pirtobrutinib with the molecular formula C22H21F4N5O3 and molecular weight of 479.44 g/mol. The chemical name for pirtobrutinib is 5-amino-3-4-[(5-fluoro-2-methoxybenzamido)methyl]phenyl-1-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-pyrazole-4-carboxamide.Pirtobrutinib is white to practically white to yellow to brown solid. The aqueous solubility of pirtobrutinib is considered practically insoluble, or insoluble, across the pH to pH range.Pirtobrutinib tablets are supplied as 50 mg or 100 mg film-coated, debossed tablets for oral administration. Each tablet contains inactive ingredients of croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose and silicon dioxide. The tablet film coating material contains FD&C Blue 2, hypromellose, titanium dioxide and triacetin.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended dosage: 200 mg orally once daily; swallow whole with water, with or without food. Do not cut, crush, or chew tablets. (2.1)Manage toxicity using treatment interruption, dosage reduction, or discontinuation. (2.2)Reduce dose in patients with severe renal impairment. (2.3, 8.6). Recommended dosage: 200 mg orally once daily; swallow whole with water, with or without food. Do not cut, crush, or chew tablets. (2.1). Manage toxicity using treatment interruption, dosage reduction, or discontinuation. (2.2). Reduce dose in patients with severe renal impairment. (2.3, 8.6). 2.1 Recommended Dosage. The recommended dosage of JAYPIRCA is 200 mg orally once daily until disease progression or unacceptable toxicity.Advise patients of the following:Swallow tablets whole with water. Do not cut, crush, or chew tablets.Take JAYPIRCA at the same time each day. JAYPIRCA may be taken with or without food.If dose of JAYPIRCA is missed by more than 12 hours, do not make up the dose and take the next dose as scheduled.. Swallow tablets whole with water. Do not cut, crush, or chew tablets.. Take JAYPIRCA at the same time each day. JAYPIRCA may be taken with or without food.. If dose of JAYPIRCA is missed by more than 12 hours, do not make up the dose and take the next dose as scheduled.. 2.2 Dosage Modifications for Adverse Reactions. Recommended dosage modifications of JAYPIRCA for adverse reactions are presented in Table [see Warnings and Precautions (5.1, 5.2, 5.3, and 5.4)].Table 1: Recommended Dosage Modification of JAYPIRCA for Adverse ReactionsDose modification is not recommended for asymptomatic lymphocytosis. Asymptomatic lipase increase may not necessarily warrant dose modification.a Evaluate the benefit-risk before resuming treatment at the same dose for Grade non-hematological toxicity.Adverse ReactionOccurrences Requiring Dosage ModificationModification(Starting Dosage: 200 mg once daily)Grade or greater non-hematologic toxicity Absolute neutrophil count 1 to 0.5 109/L with fever and/or infectionAbsolute neutrophil count 0.5 109/L lasting or more daysPlatelet count 50 to 25 109/L with bleedingPlatelet count 25 109/LFirst occurrenceInterrupt JAYPIRCA until recovery to Grade or baseline; restart at original dosage (200 mg once daily)a.Second occurrenceInterrupt JAYPIRCA until recovery to Grade or baseline; restart at 100 mg once daily.Third occurrenceInterrupt JAYPIRCA until recovery to Grade or baseline; restart at 50 mg once daily.Fourth occurrenceDiscontinue JAYPIRCA.. Grade or greater non-hematologic toxicity . Absolute neutrophil count 1 to 0.5 109/L with fever and/or infection. Absolute neutrophil count 0.5 109/L lasting or more days. Platelet count 50 to 25 109/L with bleeding. Platelet count 25 109/L. 2.3 Dosage Modifications for Patients with Severe Renal Impairment. For patients with severe renal impairment (eGFR 15-29 mL/min), reduce the JAYPIRCA dose to 100 mg once daily if the current dose is 200 mg once daily otherwise reduce the dose by 50 mg. If the current dosage is 50 mg once daily, discontinue JAYPIRCA [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. No dosage adjustment of JAYPIRCA is recommended in patients with mild to moderate renal impairment (eGFR 30-89 mL/min).. 2.4 Dosage Modifications for Concomitant Use with Strong CYP3A Inhibitors. Avoid concomitant use of strong CYP3A inhibitors with JAYPIRCA [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. If concomitant use of strong CYP3A inhibitor is unavoidable, reduce the JAYPIRCA dose by 50 mg. If the current dosage is 50 mg once daily, interrupt JAYPIRCA treatment for the duration of strong CYP3A inhibitor use. After discontinuation of strong CYP3A inhibitor for half-lives, resume the JAYPIRCA dose that was taken prior to initiating the strong CYP3A inhibitor.. 2.5 Dosage Modifications for Concomitant Use with CYP3A Inducers. Avoid concomitant use of strong or moderate CYP3A inducers with JAYPIRCA [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. If concomitant use with moderate CYP3A inducers is unavoidable and the current dosage of JAYPIRCA 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablets:Each 50 mg tablet is blue, arc-triangle shaped, film-coated, and debossed with Lilly 50 on one side and 6902 on the other side.Each 100 mg tablet is blue, round, film-coated, and debossed with Lilly 100 on one side and 7026 on the other side.. Tablets: 50 mg, 100 mg. (3).

DRUG INTERACTIONS SECTION.

7 DRUG 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). 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 InhibitorsPirtobrutinib is CYP3A substrate. Concomitant use of JAYPIRCA with strong CYP3A inhibitor increased pirtobrutinib systemic exposure [see Clinical Pharmacology (12.3)], 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 [see Dosage and Administration (2.4)].. Strong or Moderate CYP3A InducersConcomitant use of JAYPIRCA with strong or moderate CYP3A inducer decreased pirtobrutinib systemic exposure [see Clinical Pharmacology (12.3)], 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 [see Dosage and Administration (2.5)].. 7.2 Effect of JAYPIRCA on Other Drugs. Sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP SubstratesJAYPIRCA is P-gp inhibitor, moderate CYP2C8 and BCRP inhibitor, and weak CYP2C19 and CYP3A inhibitor. Concomitant use of JAYPIRCA with sensitive P-gp, CYP2C8, BCRP, CYP2C19, or CYP3A substrates increased their plasma concentrations [see Clinical Pharmacology (12.3)], 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.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Based on findings from animal studies, JAYPIRCA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating JAYPIRCA.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with JAYPIRCA and for one week after the last dose.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the patients with MCL who received the 200 mg dose of JAYPIRCA in BRUIN, 93 (78%) were 65 years of age and older and 39 (33%) were 75 years and older [see Clinical Studies (14.1)]. Clinical studies of JAYPIRCA did not include sufficient numbers of patients with MCL who were less than 65 years of age to determine whether older patients respond differently from younger adult patients.In the pooled safety population in patients with hematologic malignancies, 392 (67%) were 65 years of age and older, while 153 (26%) were 75 years of age and older. Patients aged 65 years and older experienced higher rates of Grade and higher adverse reactions and serious adverse reactions compared to patients who were less than 65 years of age.

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. No dosage adjustment of JAYPIRCA is recommended in patients with mild hepatic impairment (total bilirubin <= upper limit of normal (ULN) and aspartate aminotransferase (AST) ULN or total bilirubin 1 to 1.5 ULN and any AST), moderate hepatic impairment (total bilirubin 1.5 to x ULN and any AST), or severe hepatic impairment (total bilirubin 3 ULN and any AST) [see Clinical Pharmacology (12.3 )].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedJAYPIRCA tablets are supplied as follows:Tablet StrengthDescriptionPackage ConfigurationNDC Number50 mgBlue, film coated, arc-triangle shaped tablets debossed with Lilly 50 on one side and 6902 on the other side.Bottle with child-resistant closure.Each bottle contains 30 tablets.0002-6902-30100 mgBlue, film coated, round tablets debossed with Lilly 100 on one side and 7026 on the other side.Bottle with child-resistant closure.Each bottle contains 60 tablets.0002-7026-60Storage and HandlingStore JAYPIRCA tablets at room temperature 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F) ([see USP Controlled Room Temperature]).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. JAYPIRCA is kinase inhibitor indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including BTK inhibitor. (1.1)This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial.. 1.1 Mantle Cell Lymphoma. JAYPIRCA is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including BTK inhibitor.This indication is approved under accelerated approval based on response rate [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. InfectionsAdvise patients that JAYPIRCA can cause serious infections that may be fatal. Advise patients to report any signs or symptoms of infection (e.g., fever, chills, weakness) [see Warnings and Precautions (5.1)]. HemorrhageInform patients to report signs or symptoms of bleeding. Inform patients that JAYPIRCA may need to be interrupted for major surgeries [see Warnings and Precautions (5.2)].. CytopeniasAdvise patients of the need for periodic monitoring of blood counts during treatment with JAYPIRCA [see Warnings and Precautions (5.3)].. Atrial Fibrillation and Atrial FlutterCounsel patients to report any signs of palpitations, dizziness, fainting, chest discomfort, and shortness of breath [see Warnings and Precautions (5.4 )].. Second Primary MalignanciesInform patients that other malignancies have been reported in patients who have been treated with JAYPIRCA, including skin cancer and other solid tumors. Advise patients to use sun protection and to have monitoring for development of other cancers [see Warnings and Precautions (5.5)]. Embryo-Fetal ToxicityAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1, 8.3)]. Advise females of reproductive potential to use effective contraception during treatment with JAYPIRCA and for one week after the last dose [see Use in Specific Populations (8.3)].. LactationAdvise women not to breastfeed during treatment with JAYPIRCA and for one week after the last dose [see Use in Specific Populations (8.2)].. AdministrationInform patients to take JAYPIRCA orally once daily at approximately the same time each day with or without food and how to make up missed dose. Advise patients to swallow tablets whole with water. Advise patients not to cut, crush, or chew tablets [see Dosage and Administration (2.1)].Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USACopyright (C) 2023, Eli Lilly and Company. All rights reserved.JAY-0001-USPI-202301.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of pirtobrutinib in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with JAYPIRCA and for one week after the last dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of action. Pirtobrutinib is small molecule, noncovalent inhibitor of BTK. BTK is signaling protein of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Pirtobrutinib binds to wild type BTK and BTK harboring C481 mutations, leading to inhibition of BTK kinase activity. In nonclinical studies, pirtobrutinib inhibited BTK-mediated B-cell CD69 expression and inhibited malignant B-cell proliferation. Pirtobrutinib showed dose-dependent anti-tumor activities in BTK wild type and BTK C481S mutant mouse xenograft models.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, mutagenesis, impairment of fertility. Carcinogenicity studies have not been conducted with pirtobrutinib.Pirtobrutinib was not mutagenic in bacterial mutagenicity (Ames) assay. Pirtobrutinib was aneugenic in in vitro micronucleus assays using human peripheral blood lymphocytes. Pirtobrutinib was not genotoxic in an in vivo rat bone marrow micronucleus assay at doses up to 2000 mg/kg.Studies to assess the effects of pirtobrutinib on fertility have not been conducted. In repeat-dose toxicity studies of up to 3-months duration conducted with pirtobrutinib in rats and dogs, no effects on male or female reproductive organs were identified.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL JAYPIRCA 50 mg Tablets, 30 count bottleNDC 0002-6902-3030 tablets Rx onlyJaypircaTM (pirtobrutinib)tablets50 mgEach tablet contains 50 mg pirtobrutinibwww.jaypirca.comLilly. PACKAGE LABEL JAYPIRCA 50 mg Tablets, 30 count bottle.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of JAYPIRCA have not been established in pediatric patients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. At the recommended dosage of 200 mg once daily, pirtobrutinib trough concentrations exceeded the BTK IC96. BTK occupancy is maintained throughout the dosing interval, regardless of the intrinsic rate of BTK turnover.. Cardiac ElectrophysiologyThe effect of single 900 mg dose of pirtobrutinib (equivalent to approximately times higher than the concentrations achieved at steady state at the recommended dosage of 200 mg once daily) on the QTc interval was evaluated in placebo-controlled and positive-controlled study in 30 healthy subjects. Pirtobrutinib had no clinically meaningful effect on the change in QTcF interval (i.e., 10 ms) and there was no relationship between pirtobrutinib exposure and change in QTc interval.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of pirtobrutinib were characterized in healthy subjects and in patients with cancer. Pirtobrutinib exposure (AUC) and Cmax increases proportionally following single oral doses ranging from 300 mg to 800 mg (1.5 to times the approved recommended dosage) and once daily doses ranging from 25 300 mg (0.125 to 1.5 times the recommended dosage). Steady state was achieved within days of once daily dosing, and the mean (CV%) accumulation ratio was 1.63 (26.7%) based on AUC after administration of 200 mg dosages.Following administration of the recommended dosage, the geometric mean (CV%) steady-state AUC and Cmax of pirtobrutinib were 91300 hng/mL (41%) and 6460 ng/mL (26%), respectively. The geometric mean (CV%) AUC0-24 and Cmax of pirtobrutinib on Cycle Day were 81800 hng/mL (66.6%) and 3670 ng/mL (89.5%), respectively.. AbsorptionThe absolute bioavailability of pirtobrutinib after single oral 200 mg dose is 85.5% (range 75.9% to 90.9%). The median time (range) to reach peak plasma concentration (tmax) is approximately hours (0.833 to 4.15 hours).. Effect of FoodNo clinically significant differences in the pharmacokinetics of pirtobrutinib were observed following administration of high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) to healthy subjects. high-fat meal decreased the Cmax of pirtobrutinib by 23% and delayed tmax by hour. There was no effect on pirtobrutinib AUC.. DistributionThe mean apparent central volume of distribution of pirtobrutinib is 32.8 L. Human protein binding of pirtobrutinib is 96% and is independent of concentration in vitro. Mean blood-to-plasma ratio is 0.79.. EliminationThe effective half-life of pirtobrutinib is approximately 19 hours and the mean (CV%) apparent clearance is 2.02 L/h (37.9%).. MetabolismPirtobrutinib is primarily metabolized by CYP3A4 and direct glucuronidation by UGT1A8 and UGT1A9, in vitro.. ExcretionFollowing single radiolabeled dose of pirtobrutinib 200 mg to healthy subjects, 37% of the dose was recovered in feces (18% unchanged) and 57% in urine (10% unchanged).. Specific PopulationsThere were no clinically significant differences in the pharmacokinetics of pirtobrutinib based on age (range 27 95 years), sex, race/ethnicity (White 86%, Asian 7%), body weight (range 35.7 152.5 kg), mild (total bilirubin <= upper limit of normal (ULN) and aspartate aminotransferase (AST) ULN or total bilirubin 1 to 1.5 ULN and any AST), moderate (total bilirubin 1.5 to x ULN and any AST), or severe (total bilirubin 3 ULN and any AST) hepatic impairment. The effect of other races/ethnicities on the pharmacokinetics of pirtobrutinib is unknown.. Patients with Renal ImpairmentFollowing single 200 mg oral dose, the AUC of pirtobrutinib in subjects with severe renal impairment (eGFR 15-29 mL/min) increased by 62% and mean unbound AUC increased by 68% compared to healthy subjects with normal renal function. There were no clinically significant differences in the pharmacokinetics of pirtobrutinib in subjects with mild (eGFR 60-89 mL/min) or moderate renal impairment (eGFR 30-59 mL/min). The effect of renal impairment requiring dialysis on the pharmacokinetics of pirtobrutinib is unknown.. Drug Interaction Studies. Clinical Studies and Model-Informed ApproachesStrong CYP3A Inhibitors: Co-administration of single 200 mg dose of pirtobrutinib with itraconazole (strong CYP3A inhibitor) increased AUC of pirtobrutinib by 49%.Moderate CYP3A Inhibitors: Verapamil and diltiazem (moderate CYP3A inhibitors) are predicted to increase the AUC of pirtobrutinib by 30% and 20%, respectively.Strong CYP3A inducers: Coadministration of single 200 mg dose of pirtobrutinib with rifampin (strong CYP3A inducer) decreased the AUC of pirtobrutinib by 71%.Moderate CYP3A Inducers: Efavirenz and bosentan (moderate CYP3A inducers) are predicted to decrease the AUC of pirtobrutinib by 49% and 27%, respectively.Gastric Reducing Agents: No clinically significant differences in pirtobrutinib pharmacokinetics were observed when co-administered with omeprazole (a proton pump inhibitor).P-glycoprotein (P-gp) inhibitors: No clinically significant differences in pirtobrutinib pharmacokinetics were observed when co-administered with itraconazole (P-gp inhibitor).CYP3A Substrates: Pirtobrutinib increased the AUC and Cmax of orally administered midazolam (sensitive CYP3A substrate) by 70% and 58%, respectively. Pirtobrutinib did not have clinically meaningful effect on the exposure of intravenously administered midazolam.CYP2C8 Substrates: Pirtobrutinib increased the AUC and Cmax of repaglinide (sensitive CYP2C8 substrate) by 130% and 98%, respectively.CYP2C19 Substrates: Pirtobrutinib increased the AUC and Cmax of omeprazole (sensitive CYP2C19 substrate) by 56% and 49%, respectively.P-gp Substrates: single 200 mg dose of pirtobrutinib increased the AUC and Cmax of digoxin (sensitive P-gp substrate) by 17% and 51%, respectively. Multiple doses of pirtobrutinib (200 mg daily) further increased the AUC and Cmax of digoxin (sensitive P-gp substrate) up to 35% and 55%, respectively.BCRP Substrates: Multiple doses of pirtobrutinib (200 mg daily) increased the AUC and Cmax of rosuvastatin (sensitive BCRP substrate) by 140% and 146%, respectively.CYP1A2 and CYP2C9 Substrates: Pirtobrutinib did not have clinically meaningful effect on the exposures of caffeine (sensitive CYP1A2 substrate) or S-warfarin (moderate sensitive CYP2C9 substrate).. In Vitro StudiesCytochrome P450 (CYP) Enzymes: Pirtobrutinib inhibits CYP2C8, CYP2C9, CYP3A, CYP1A2, CYP2B6, CYP2C19, and CYP2D6. Pirtobrutinib induces CYP3A4, CYP3A5, CYP2B6, and CYP2C19.Transporter Systems: Pirtobrutinib inhibits P-gp and BCRP, but not OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K. Pirtobrutinib is not substrate of the hepatic transporters. Pirtobrutinib is substrate of P-gp and BCRP, but not OCT1, OATP1B1, OATP1B3, or BSEP.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings from animal studies, JAYPIRCA can cause fetal harm when administered to pregnant woman. There are no available data on JAYPIRCA use in pregnant women to evaluate for drug-associated risk. In an animal reproduction study, administration of pirtobrutinib to pregnant rats during organogenesis resulted in adverse developmental outcomes, including structural abnormalities, altered fetal growth, and embryo-fetal mortality, at maternal exposures approximately 3-times those in patients at the recommended daily dose of 200 mg (see Data). Advise pregnant women of the potential risk to fetus.The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.. Data. Animal DataIn an embryo-fetal development study in rats, pregnant animals were administered oral doses of pirtobrutinib at up to 500 mg/kg twice daily during the period of organogenesis. Doses >= 375 mg/kg twice daily caused decreased fetal body weights and increased incidence of malformations and variations in the urinary tract (including absent or abnormal ureters and kidneys), reproductive tract (malpositioned ovaries and misshapen uterus), and bone (misshapen sternebrae). At 500 mg/kg twice daily, total resorption was observed. At 375 mg/kg twice daily in rats, the maternal systemic exposures (AUC) were approximately times the human exposure at 200 mg once daily.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. Severe renal impairment (eGFR15-29 mL/min) increases pirtobrutinib exposure [see Clinical Pharmacology (12.3)]. Reduce the JAYPIRCA dosage in patients with severe renal impairment [see Dosage and Administration (2.3)]. No dosage adjustment of JAYPIRCA is recommended in patients with mild (60-89 mL/min) or moderate (30-59 mL/min) renal impairment.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 1/2023PATIENT INFORMATIONJAYPIRCA(TM) (JAY-PIHR-KAA)pirtobrutinibtabletsWhat is JAYPIRCAJAYPIRCA is prescription medicine used to treat adults with mantle cell lymphoma (MCL) that has come back or did not respond to previous treatment, and who have already received two or more treatments for their cancer, including Bruton tyrosine kinase (BTK) inhibitor medicine.It is not known if JAYPIRCA is safe and effective in children.Before taking JAYPIRCA, tell your healthcare provider about all of your medical conditions, including if you:have an infection or have been advised that you are at increased risk of infectionhave had recent surgery or plan to have surgery. Your healthcare provider may stop JAYPIRCA for any planned medical, surgical, or dental procedure.have bleeding problems or are taking blood thinner medicinehave or had heart rhythm problemshave high blood pressurehave history of other cancers including skin cancerhave kidney problemsare pregnant or plan to become pregnant. JAYPIRCA can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will do pregnancy test before starting treatment with JAYPIRCA.You should use effective birth control (contraception) during treatment with JAYPIRCA and for week after your last dose of JAYPIRCA.Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with JAYPIRCA. are breastfeeding or plan to breastfeed. It is not known if JAYPIRCA passes into your breast milk. Do not breastfeed during treatment with JAYPIRCA and for week after your last dose of JAYPIRCA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking JAYPIRCA with certain other medicines may affect how JAYPIRCA or the other medicines work and can cause side effects.How should take JAYPIRCATake JAYPIRCA exactly as your healthcare provider tells you.Do not change your dose or stop taking JAYPIRCA unless your healthcare provider tells you to do so.Take JAYPIRCA tablets time each day at about the same time each day.Take JAYPIRCA with or without food.Swallow JAYPIRCA tablets whole with water. Do not cut, crush, or chew the tablets.If you miss dose of JAYPIRCA, take it as soon as you remember on the same day. If it has been more than 12 hours from the time you usually take JAYPIRCA, skip the missed dose, and take your next dose on the next day at your usual time.What are the possible side effects of JAYPIRCAJAYPIRCA can cause serious side effects, including:Infections can happen during treatment with JAYPIRCA. These infections can be serious and may lead to death. Your healthcare provider may prescribe certain medicines if you have an increased risk of getting infections. Tell your healthcare provider right away if you develop fever, chills, weakness, flu-like symptoms, or any other signs of infection during treatment with JAYPIRCA.Bleeding problems (hemorrhage) can happen during treatment with JAYPIRCA and can be serious and may lead to death. Your risk of severe bleeding may increase if you are also taking blood thinner medicine. Tell your healthcare provider if you develop any signs or symptoms of bleeding, including:blood in your stools or black stools (looks like tar)pink or brown urineunexpected bleeding, or bleeding that is severe or you cannot controlvomit blood or vomit blood that looks like coffee grindscough up blood or blood clotsincreased bruisingdizzinessweaknessconfusionchanges in your speechheadache that lasts long timeDecrease in blood cell counts. Decrease in blood cell counts (white blood cells, platelets, and red blood cells) are common with JAYPIRCA, but can also be severe. This may increase your risk of infection, bleeding, and anemia. Your healthcare provider should do blood tests to check your blood counts regularly during treatment with JAYPIRCA.Heart rhythm problems (atrial fibrillation and atrial flutter) have happened in people treated with JAYPIRCA. Your risk for heart rhythm problems may be increased if you have high blood pressure or have had heart rhythm problems in the past. Tell your healthcare provider if you develop any of the following signs or symptoms:fast or irregular heartbeat (palpitations)dizzinessfaintingchest discomfortshortness of breathSecond primary cancers. New cancers have happened in people during treatment with JAYPIRCA, including cancers of the skin or other organs. Your healthcare provider will check you for other cancers during treatment with JAYPIRCA. Use sun protection when you are outside in sunlight.Your healthcare provider may decrease your dose, temporarily stop, or permanently stop treatment with JAYPIRCA if you develop severe side effects. The most common side effects of JAYPIRCA include: tirednessmuscle, joint, and bone paindiarrheaswellingshortness of breathpneumoniabruisingThese are not all the possible side effects of JAYPIRCA.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store JAYPIRCAStore JAYPIRCA at room temperature between 68F to 77F (20C to 25C).JAYPIRCA comes in bottle with child-resistant cap.Keep JAYPIRCA and all medicines out of the reach of children.General information about the safe and effective use of JAYPIRCA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use JAYPIRCA for condition for which it was not prescribed. Do not give JAYPIRCA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about JAYPIRCA that is written for health professionals.What are the ingredients in JAYPIRCAActive ingredient: pirtobrutinib Inactive ingredients: croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and silicon dioxide. The tablet film coating contains FD&C Blue 2, hypromellose, titanium dioxide, and triacetin. Marketed by Lilly USA, LLC, Indianapolis, IN 46285, USA JAYPIRCA is trademark of Eli Lilly and Company.Copyright (C) 2023, Eli Lilly and Company. All rights reserved.JAY-0001-PPI-202301 For more information, go to www.jaypirca.com or call 1-800-LillyRx (1-800-545-5979).. have an infection or have been advised that you are at increased risk of infection. have had recent surgery or plan to have surgery. Your healthcare provider may stop JAYPIRCA for any planned medical, surgical, or dental procedure.. have bleeding problems or are taking blood thinner medicine. have or had heart rhythm problems. have high blood pressure. have history of other cancers including skin cancer. have kidney problems. are pregnant or plan to become pregnant. JAYPIRCA can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will do pregnancy test before starting treatment with JAYPIRCA.You should use effective birth control (contraception) during treatment with JAYPIRCA and for week after your last dose of JAYPIRCA.Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with JAYPIRCA. Your healthcare provider will do pregnancy test before starting treatment with JAYPIRCA.. You should use effective birth control (contraception) during treatment with JAYPIRCA and for week after your last dose of JAYPIRCA.. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with JAYPIRCA.. are breastfeeding or plan to breastfeed. It is not known if JAYPIRCA passes into your breast milk. Do not breastfeed during treatment with JAYPIRCA and for week after your last dose of JAYPIRCA. Take JAYPIRCA exactly as your healthcare provider tells you.. Do not change your dose or stop taking JAYPIRCA unless your healthcare provider tells you to do so.. Take JAYPIRCA tablets time each day at about the same time each day.. Take JAYPIRCA with or without food.. Swallow JAYPIRCA tablets whole with water. Do not cut, crush, or chew the tablets.. If you miss dose of JAYPIRCA, take it as soon as you remember on the same day. If it has been more than 12 hours from the time you usually take JAYPIRCA, skip the missed dose, and take your next dose on the next day at your usual time.. Infections can happen during treatment with JAYPIRCA. These infections can be serious and may lead to death. Your healthcare provider may prescribe certain medicines if you have an increased risk of getting infections. Tell your healthcare provider right away if you develop fever, chills, weakness, flu-like symptoms, or any other signs of infection during treatment with JAYPIRCA.. Bleeding problems (hemorrhage) can happen during treatment with JAYPIRCA and can be serious and may lead to death. Your risk of severe bleeding may increase if you are also taking blood thinner medicine. Tell your healthcare provider if you develop any signs or symptoms of bleeding, including:. blood in your stools or black stools (looks like tar). pink or brown urine. unexpected bleeding, or bleeding that is severe or you cannot control. vomit blood or vomit blood that looks like coffee grinds. cough up blood or blood clots. increased bruising. dizziness. weakness. confusion. changes in your speech. headache that lasts long time. Decrease in blood cell counts. Decrease in blood cell counts (white blood cells, platelets, and red blood cells) are common with JAYPIRCA, but can also be severe. This may increase your risk of infection, bleeding, and anemia. Your healthcare provider should do blood tests to check your blood counts regularly during treatment with JAYPIRCA.. Heart rhythm problems (atrial fibrillation and atrial flutter) have happened in people treated with JAYPIRCA. Your risk for heart rhythm problems may be increased if you have high blood pressure or have had heart rhythm problems in the past. Tell your healthcare provider if you develop any of the following signs or symptoms:. fast or irregular heartbeat (palpitations). dizziness. fainting. chest discomfort. shortness of breath. Second primary cancers. New cancers have happened in people during treatment with JAYPIRCA, including cancers of the skin or other organs. Your healthcare provider will check you for other cancers during treatment with JAYPIRCA. Use sun protection when you are outside in sunlight.. tiredness. muscle, joint, and bone pain. diarrhea. swelling. shortness of breath. pneumonia. bruising. Store JAYPIRCA at room temperature between 68F to 77F (20C to 25C).. JAYPIRCA comes in bottle with child-resistant cap.

SPL UNCLASSIFIED SECTION.

1.1 Mantle Cell Lymphoma. JAYPIRCA is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including BTK inhibitor.This indication is approved under accelerated approval based on response rate [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings from animal studies, JAYPIRCA can cause fetal harm when administered to pregnant woman. There are no available data on JAYPIRCA use in pregnant women to evaluate for drug-associated risk. In an animal reproduction study, administration of pirtobrutinib to pregnant rats during organogenesis resulted in adverse developmental outcomes, including structural abnormalities, altered fetal growth, and embryo-fetal mortality, at maternal exposures approximately 3-times those in patients at the recommended daily dose of 200 mg (see Data). Advise pregnant women of the potential risk to fetus.The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.. Data. Animal DataIn an embryo-fetal development study in rats, pregnant animals were administered oral doses of pirtobrutinib at up to 500 mg/kg twice daily during the period of organogenesis. Doses >= 375 mg/kg twice daily caused decreased fetal body weights and increased incidence of malformations and variations in the urinary tract (including absent or abnormal ureters and kidneys), reproductive tract (malpositioned ovaries and misshapen uterus), and bone (misshapen sternebrae). At 500 mg/kg twice daily, total resorption was observed. At 375 mg/kg twice daily in rats, the maternal systemic exposures (AUC) were approximately times the human exposure at 200 mg once daily.. 8.2 Lactation. Risk SummaryThere are no data on the presence of pirtobrutinib in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with JAYPIRCA and for one week after the last dose.. 8.3 Females and Males of Reproductive Potential. Based on findings from animal studies, JAYPIRCA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating JAYPIRCA.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with JAYPIRCA and for one week after the last dose.. 8.4 Pediatric Use. Safety and effectiveness of JAYPIRCA have not been established in pediatric patients.. 8.5 Geriatric Use. Of the patients with MCL who received the 200 mg dose of JAYPIRCA in BRUIN, 93 (78%) were 65 years of age and older and 39 (33%) were 75 years and older [see Clinical Studies (14.1)]. Clinical studies of JAYPIRCA did not include sufficient numbers of patients with MCL who were less than 65 years of age to determine whether older patients respond differently from younger adult patients.In the pooled safety population in patients with hematologic malignancies, 392 (67%) were 65 years of age and older, while 153 (26%) were 75 years of age and older. Patients aged 65 years and older experienced higher rates of Grade and higher adverse reactions and serious adverse reactions compared to patients who were less than 65 years of age.. 8.6 Renal Impairment. Severe renal impairment (eGFR15-29 mL/min) increases pirtobrutinib exposure [see Clinical Pharmacology (12.3)]. Reduce the JAYPIRCA dosage in patients with severe renal impairment [see Dosage and Administration (2.3)]. No dosage adjustment of JAYPIRCA is recommended in patients with mild (60-89 mL/min) or moderate (30-59 mL/min) renal impairment.. 8.7 Hepatic Impairment. No dosage adjustment of JAYPIRCA is recommended in patients with mild hepatic impairment (total bilirubin <= upper limit of normal (ULN) and aspartate aminotransferase (AST) ULN or total bilirubin 1 to 1.5 ULN and any AST), moderate hepatic impairment (total bilirubin 1.5 to x ULN and any AST), or severe hepatic impairment (total bilirubin 3 ULN and any AST) [see Clinical Pharmacology (12.3 )].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS 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) Atrial Fibrillation and Atrial Flutter: 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) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to fetus and to use effective contraception. (5.6, 8.1, 8.3). 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). Atrial Fibrillation and Atrial Flutter: 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). Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to fetus and to use effective contraception. (5.6, 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. In the clinical trial, Grade or higher infections occurred in 17% of 583 patients, most commonly pneumonia (9%), with fatal infections occurring in 4.1% of patients. Sepsis occurred in 4.5% of patients and febrile neutropenia in 2.9%. Opportunistic infections after treatment with JAYPIRCA have included, but are not limited to, Pneumocystis jirovecii pneumonia and fungal infection.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 [see Dosage and Administration (2.2)].. 5.2 Hemorrhage. Fatal and serious hemorrhage has occurred with JAYPIRCA. Major hemorrhage (defined as Grade or higher bleeding or any central nervous system bleeding) occurred in 2.4% of 583 patients treated with JAYPIRCA, including gastrointestinal hemorrhage; fatal hemorrhage occurred in 0.2% of patients. Bleeding of any grade, excluding bruising and petechiae, occurred in 14% of patients.Major hemorrhage occurred in 1.7% of patients taking JAYPIRCA without antithrombotic agents and 0.7% 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 [see Dosage and Administration (2.2)].Consider the benefit-risk of withholding JAYPIRCA for to days pre- and post-surgery depending upon the type of surgery and risk of bleeding.. 5.3 Cytopenias. Grade or cytopenias, including neutropenia (24%), anemia (11%), and thrombocytopenia (11%) have developed in patients treated with JAYPIRCA. In the clinical trial, Grade neutropenia developed in 13% of patients and Grade thrombocytopenia developed in 5% of patients.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 Atrial Fibrillation and Atrial Flutter. Atrial fibrillation and atrial flutter were reported in recipients of JAYPIRCA. Atrial fibrillation or flutter were reported in 2.7% of patients, with Grade or atrial fibrillation or flutter reported in 1.0% of 583 patients in the clinical trial. 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 [see Dosage and Administration (2.2)].. 5.5 Second Primary Malignancies. Second primary malignancies, including non-skin carcinomas, developed in 6% of 583 patients treated with JAYPIRCA monotherapy. The most frequent malignancy was non-melanoma skin cancer, reported in 3.8% of 583 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 Embryo-Fetal Toxicity. Based on findings in animals, JAYPIRCA can cause fetal harm when administered to 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 fetus. Advise females of reproductive potential to use effective contraception during treatment with JAYPIRCA and for one week after the last dose [see Use in Specific Populations (8.1, 8.3)].