DRUG INTERACTIONS-(summary

 • Strong CYP3A Inhibitors: Avoid concomitant use. If concomitant use is unavoidable, reduce the JAYPIRCA dose.

 • Strong or Moderate CYP3A Inducers: Avoid concomitant use. If concomitant use of moderate CYP3A inducers is unavoidable, increase the JAYPIRCA dose.

 • 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 coadministration with CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP inhibitors provided in their approved product labeling. 

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BRIEF SUMMARY

JAYPIRCA- (Jan 2023)-

Indication-  To  treat relapsed or refractory mantle cell   lymphoma in adults who have had two ines of systemic therapy.         

Dosage-  Tablets: 50 mg, 100 mg. Recommended dosage: 200 mg orally once daily; swallow whole with water, with or without food do not crush, or chew tablets

ADR- Most common adverse reactions (= 15%) in patients with MCL are fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising

CI-  None.

WARNINGS- • Infections: Monitor for signs and symptoms of infection, evaluate promptly, and : Monitor for bleeding and manage appropriately.

Pat inform-Advise patients that it  can cause serious infections that may be fatal. Advise patients to report any signs or symptoms of infection 

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 3

Name-        JAYPIRCA

Acive  Ingredient -  Pirtobrutinib

Pharmacological clssificiation-        To  treat relapsed or refractory mantle cell                                                                      lymphoma in adults who have had at least                                                                    two lines of systemic therapy, including a                                                                      BTK inhibitor                                                                                                                                                                                                        

 Date of Approval-         1/27/2023

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                     JAYPIRCA safely and effectively.                                                                                   See full prescribing information for JAYPIRCA. JAYPIRCATM (pirtobrutinib) tablets, for oral use.

Initial U.S. Approval: 2023

 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 inh bitor.

 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.

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.

DOSAGE FORMS AND STRENGTHS-

 Tablets: 50 mg, 100 mg.

CONTRAINDICATIONS-                                                                                                   None.

WARNINGS AND PRECAUTIONS --

 • Infections: Monitor for signs and symptoms of infection, evaluate promptly, and treat.

 • Hemorrhage: Monitor for bleeding and manage appropriately.

• Cytopenias: Monitor complete blood counts during treatment.

 • Atrial Fibrillation and Atrial Flutter: Monitor for symptoms of arrhythmias and manage appropriately.

ADVERSE REACTIONS-

 Most common adverse reactions (= 15%) in patients with MCL are fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities (= 10%) are neutrophil count decreased, lymphocyte count decreased, and platelet count decreased.

CONTRAINDICATIONS-                                                                                                   None.

WARNINGS AND PRECAUTIONS --

 • Infections: Monitor for signs and symptoms of infection, evaluate promptly, and treat.

 • Hemorrhage: Monitor for bleeding and manage appropriately.

• Cytopenias: Monitor complete blood counts during treatment.

 • Atrial Fibrillation and Atrial Flutter: Monitor for symptoms of arrhythmias and manage appropriately.

 •Second Primary Malignancies: Other malignancies have developed, including skin cancers and other carcinomas. Monitor and advise patients to use sun protection.

 • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception.

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.

DOSAGE FORMS AND STRENGTHS-

 Tablets: 50 mg, 100 mg.

PATIENT COUNSELING INFORMATION -

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Infections -                                                                                                                 Advise 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).

Hemorrhage-                                                                                                             Inform patients to report signs or symptoms of bleeding. Inform patients that JAYPIRCA may need to be interrupted for major surgeries.

Cytopenias -                                                                                                                Advise patients of the need for periodic monitoring of blood counts during treatment with JAYPIRCA.

Atrial Fibrillation and Atrial Flutter-                                                                              Counsel patients to report any signs of palpitations, dizziness, fainting, chest discomfort, and shortness of breath.

Second Primary Malignancies-                                                                                        Inform 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.

 Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

Use in Specific Populations-                                                                                  Advise females of reproductive potential to use effective contraception during treatment with JAYPIRCA and for one week after the last dose.

Lactation- Advise women not to breastfeed during treatment with JAYPIRCA and for one week after the last dose.

 Administration- Inform patients to take JAYPIRCA orally once daily at approximately the same time each day with or without food and how to make up a missed dose.

Advise patients to swallow tablets whole with water. Advise patients not to cut, crush, or chew tablets.

JAYPIRCA-Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2023, Eli Lilly and Company. All rights reserved. JAY-0001-USPI-202301DD Reference ID: 5116752 PATIENT INFORMATION

CLINICAL PHARMACOLOGY

1. Mechanism of action-                                                                                         Pirtobrutinib is a small molecule, noncovalent inhibitor of BTK. BTK is a 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

Cardiac Electrophysiology -                                                                                        The effect of a single 900 mg dose of pirtobrutinib (equivalent to approximately 2 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 a placebo-controlled and positive-controlled study in 30 healthy subjects.

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 4 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 5 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 h*ng/mL (41%) and 6460 ng/mL (26%), respectively.

The geometric mean (CV%) AUC0-24 and Cmax of pirtobrutinib on Cycle 1 Day 8 were 81800 h*ng/mL (66.6%) and 3670 ng/mL (89.5%), respectively.

Absorption-                                                                                                                   The absolute bioavailability of pirtobrutinib after a 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 2 hours (0.833 to 4.15 hours).

Effect of Food-                                                                                                               No clinically significant differences in the pharmacokinetics of pirtobrutinib were observed following administration of a 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.

A high-fat meal decreased the Cmax of pirtobrutinib by 23% and delayed tmax by 1 hour. There was no effect on pirtobrutinib AUC.

Distribution-                                                                                                                  The 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. Elimination The effective half-life of pirtobrutinib is approximately 19 hours and the mean (CV%) apparent clearance is 2.02 L/h (37.9%).

Metabolism-                                                                                                               Pirtobrutinib is primarily metabolized by CYP3A4 and direct glucuronidation by UGT1A8 and UGT1A9, in vitro.

Excretion-                                                                                                                     Following a 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 Populations There 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 Reference ID: 5116752 10 (total bilirubin > 1.5 to 3 × 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 Impairment Following a 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 unknow

Drug Interaction Studies-                                                                                            Clinical Studies and Model-Informed Approaches Strong CYP3A Inhibitors: Co-administration of a 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 a 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 a 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: A 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 a clinically meaningful effect on the exposures of caffeine (sensitive CYP1A2 substrate) or S-warfarin (moderate sensitive CYP2C9 substrate).

In Vitro Studies Cytochrome 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 a substrate of the hepatic transporters. Pirtobrutinib is a substrate of P-gp and BCRP, but not OCT1, OATP1B1, OATP1B3, or BSEP.

USE IN SPECIFIC POPULATIONS-

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.

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.

2 Lactation Risk Summary-                                                                                      There 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.

3. Females and Males of Reproductive Potential-                                                     Based on findings from animal studies, JAYPIRCA can cause fetal harm when administered to a pregnant woman.

Pregnancy Testing- Verify pregnancy status in females of reproductive potential prior to initiating JAYPIRCA.

Contraception- Females-                                                                                               Advise females of reproductive potential to use effective contraception during treatment with JAYPIRCA and for one week after the last dose.

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

.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 .

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 3 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.

Reduce the JAYPIRCA dosage in patients with severe renal impairment.

No dosage adjustment of JAYPIRCA is recommended in patients with mild (60-89 mL/min) or moderate (30-59 mL/min) renal impairment.

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 3 × ULN and any AST), or severe hepatic impairment (total bilirubin > 3 × ULN and any AST) [see Clinical Pharmacology (12.3)].