Pirtobrutinib

FDA Drug Information • Also known as: Jaypirca

Brand Names: Jaypirca
Dosage Form: POWDER
Product Type: BULK INGREDIENT

Description

11 DESCRIPTION Pirtobrutinib is a kinase inhibitor. It is an orally available, small molecule ATP-competitive inhibitor of BTK. The active pharmaceutical ingredient is pirtobrutinib with the molecular formula C 22 H 21 F 4 N 5 O 3 and a molecular weight of 479.44 g/mol. The chemical name for pirtobrutinib is 5-amino-3-{4-[(5-fluoro-2-methoxybenzamido)methyl]phenyl}-1-[(2 S )-1,1,1-trifluoropropan-2-yl]-1 H -pyrazole-4-carboxamide. Pirtobrutinib is a white to practically white to yellow to brown solid. The aqueous solubility of pirtobrutinib is considered practically insoluble, or insoluble, across the pH 1 to pH 7 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

What Is Pirtobrutinib Used For?

1 INDICATIONS AND USAGE JAYPIRCA ® is a 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 a 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 a confirmatory trial. Adult patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have previously been treated with a covalent BTK inhibitor. ( 1.2 ). 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 a 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 a confirmatory trial. 1.2 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma JAYPIRCA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have previously been treated with a covalent BTK inhibitor.

Dosage and Administration

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 ) 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 a 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 1 [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 , and 5.4 )] . Table 1: Recommended Dosage Modification of JAYPIRCA for Adverse Reactions Dose 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 a Grade 4 non-hematological toxicity. Adverse Reaction Occurrences Requiring Dosage Modification Modification (Starting Dosage: 200 mg once daily) Grade 3 or greater non-hematologic toxicity a Absolute neutrophil count < 1 to 0.5 x 10 9 /L with fever and/or infection Absolute neutrophil count < 0.5 x 10 9 /L lasting 7 or more days Platelet count < 50 to 25 x 10 9 /L with bleeding Platelet count < 25 x 10 9 /L First occurrence Interrupt JAYPIRCA until recovery to Grade 1 or baseline; restart at original dosage (200 mg once daily) a . Second occurrence Interrupt JAYPIRCA until recovery to Grade 1 or baseline; restart at 100 mg once daily. Third occurrence Interrupt JAYPIRCA until recovery to Grade 1 or baseline; restart at 50 mg once daily. Fourth occurrence Discontinue JAYPIRCA. 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 a 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...

Side Effects (Adverse Reactions)

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 )] Hepatotoxicity, including DILI [see Warnings and Precautions ( 5.6 )] Most common adverse reactions (≥ 30%), including laboratory abnormalities, are fatigue, neutrophil count decreased, platelet count decreased, hemoglobin decreased, leukocytes decreased, lymphocyte count decreased and calcium 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 a 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 a single-agent, administered at 200 mg once daily in 704 patients with hematologic malignancies in the BRUIN and the BRUIN-CLL-321 studies. Among these 704 patients, the median duration of exposure was 12 months; 65% were exposed for at least 6 months and 50% were exposed for at least one year. In this pooled safety population, the most common (≥ 30%) adverse reactions, including laboratory abnormalities, were decreased neutrophil count (54%), decreased hemoglobin (43%), decreased leukocytes (32%), fatigue (31%), decreased platelets (31%), decreased lymphocyte count (31%), and calcium decreased (30%) Mantle Cell Lymphoma BRUIN The safety of JAYPIRCA was evaluated in the BRUIN trial, an open-label, multicohort, single-arm study in patients with previously treated MCL who received a prior BTK inhibitor [see Clinical Studies ( 14.1 ) ] . The trial required a platelet count ≥ 50 x 10 9 /L, absolute neutrophil count ≥ 0.75 x 10 9 /L, hepatic transaminases ≤ 2.5 times upper limit of normal (ULN), and an ECOG performance status of 0 to 2. The trial excluded patients with active central nervous system (CNS) involvement by lymphoma, significant cardiovascular disease, major bleeding or grade ≥ 3 arrhythmia with a prior BTK inhibitor, prolonged QTc interval, or need for a 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 6 months or longer and 10% were exposed for at least one year. The median number of prior therapies was 3 (range: 1-9). The median age was 71 years (range: 46 to 88 years) and 80% of patients were male. Race was reported for all patients; 78% were White, 14% were Asian, 2.3% were Black, and 2.3% were Hispanic or Latino. 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 dose 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,...

Drug Interactions

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 ) 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 [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 Inducers Concomitant use of JAYPIRCA with a 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 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 [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.

Contraindications

4 CONTRAINDICATIONS None. None ( 4 ).

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Based on findings from animal studies, JAYPIRCA can cause fetal harm when administered to a pregnant woman. There are no available data on JAYPIRCA use in pregnant women to evaluate for a 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 a 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 Data In 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 3 times the human exposure at 200 mg once daily.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied JAYPIRCA tablets are supplied as follows: Tablet Strength Description Package Configuration NDC Number 50 mg Blue, 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. 0002-6902-30 100 mg Blue, 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. 0002-7026-60 Storage and Handling Store JAYPIRCA tablets at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) ([see USP Controlled Room Temperature]).

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.