pirtobrutinib (Rx)

Brand and Other Names:Jaypirca
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

tablet

  • 50mg
  • 100mg

Mantle Cell Lymphoma

Indicated for relapsed or refractory mantle cell lymphoma (MCL) after at least 2 lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor

200 mg PO qDay

Continue until disease progression or unacceptable toxicity

Dosage Modifications

Asymptomatic lymphocytosis: Dose modification not recommended

Asymptomatic lipase increase: May not necessarily warrant a dose modification

Hematologic toxicities

  • NOTE: Based on starting dose of 200 mg qDay
  • Absolute neutrophil count (ANC) 0.5 to <1 x 109/L with fever and/or infection
  • ANC <0.5 x 109/L lasting ≥7 days
  • Platelet count 25 to <50 x 109/L with bleeding
  • Platelet count <25 x 109/L
  • Modification
    • First occurrence: Interrupt therapy until recovery to Grade 1 or baseline; restart at original dose (200 mg qDay)
    • Second occurrence: Interrupt therapy until recovery to Grade 1 or baseline; restart at 100 mg qDay
    • Third occurrence: Interrupt therapy until recovery to Grade 1 or baseline; restart at 50 mg qDay
    • Fourth occurrence: Discontinue treatment

Nonhematologic toxicities

  • Grade ≥3 nonhematologic toxicity
  • Evaluate benefit-risk before resuming at same dose for a Grade 4 nonhematologic toxicity
  • First occurrence: Interrupt therapy until recovery to Grade 1 or baseline; restart at original dose (200 mg qDay)
  • Second occurrence: Interrupt therapy until recovery to Grade 1 or baseline; restart at 100 mg qDay
  • Third occurrence: Interrupt therapy until recovery to Grade 1 or baseline; restart at 50 mg qDay
  • Fourth occurrence: Discontinue treatment

Coadministration with strong CYP3A inhibitors

  • Avoid coadministration
  • If unavoidable, reduce pirtobrutinib to 50 mg
  • If current pirtobrutinib dose is 50 mg qDay, discontinue treatment for the duration of strong CYP3A inhibitor use
  • After strong CYP3A inhibitor has been discontinued for 5 half-lives, resume pirtobrutinib at the dose taken before the strong CYP3A inhibitor was initiated

Coadministration with strong or moderate CYP3A inducers

  • Avoid coadministration
  • If coadministration with moderate CYP3A inducers is unavoidable
    • Current pirtobrutinib dose is 200 mg qDay: Increase to 300 mg qDay
    • Current pirtobrutinib dose is 50 mg or 100 mg qDay: Increase dose by 50 mg

Renal impairment

  • Mild-to-moderate (eGFR 30-89 mL/min): No dosage adjustment necessary
  • Severe (eGFR 15-29 mL/min)
    • Current dose is 200 mg qDay: Reduce to 100 mg qDay
    • Current dose is 100 mg qDay: Reduce to 50 mg qDay
    • Current dose is 50 mg qDay: Discontinue treatment
  • Patients on dialysis: Pharmacokinetics are unknown

Hepatic impairment

  • All severities: No dosage adjustment necessary

Dosing Considerations

Verify pregnancy status in females of reproductive potential before initiating

Safety and efficacy not established

Studies did not include enough patients with MCL aged <65 years to compare the differences in effect in relation to age

Patients aged ≥65 years experienced higher rates of Grade ≥3 adverse reactions and serious adverse reactions compared with patients aged <65 years

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Interactions

Interaction Checker

and pirtobrutinib

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                    Adverse Effects

                    >10%

                    All grades

                    • Hemoglobin decreased (42%)
                    • Platelet count decreased (39%)
                    • Neutrophil count decreased (36%)
                    • Lymphocyte count decreased (32%)
                    • Creatinine increased (30%)
                    • Fatigue (29%)
                    • Musculoskeletal pain (27%)
                    • Edema (19%)
                    • Diarrhea (19%)
                    • Calcium decreased (19%)
                    • Dyspnea (17%)
                    • AST increased (17%)
                    • Cough (16%)
                    • Bruising (16%)
                    • Pneumonia (16%)
                    • Peripheral neuropathy (14%)
                    • Rash (14%)
                    • Fever (13%)
                    • Constipation (13%)
                    • Potassium decreased (13%)
                    • Sodium decreased (13%)
                    • Lipase increased (12%)
                    • Arthritis or arthralgia (12%)
                    • Abdominal pain (11%)
                    • Nausea (11%)
                    • Hemorrhage (11%)
                    • Alkaline phosphatase increased (11%)
                    • ALT increased (11%)
                    • Potassium increased (11%)

                    Grade 3-4

                    • Neutrophil count decreased (16%)
                    • Lymphocyte count decreased (15%)
                    • Pneumonia (14%)
                    • Platelet count decreased (14%)

                    1-10%

                    All grades

                    • Upper respiratory tract infections (10%)
                    • Dizziness (10%)

                    Grade 3-4

                    • Hemoglobin decreased (9%)
                    • Lipase increased (4.4%)
                    • Musculoskeletal pain (3.9%)
                    • Hemorrhage (3.1%)
                    • Dyspnea (2.3%)
                    • Fatigue (1.6%)
                    • ALT or AST increased (1.6%)
                    • Creatinine increased (1.6%)
                    • Calcium decreased (1.6%)
                    • Potassium decreased (1.6%)

                    <1%

                    Grade 3-4

                    • Edema (0.8%)
                    • Arthritis or arthralgia (0.8%)
                    • Abdominal pain (0.8%)
                    • Upper respiratory tract infections (0.8%)
                    • Peripheral neuropathy (0.8%)
                    • Potassium increased (0.8%)
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                    Warnings

                    Contraindications

                    None

                    Cautions

                    For all adverse reactions, based on severity, reduce dose, temporarily withhold, or permanently discontinue

                    Grade 3 or 4 cytopenias, including neutropenia, anemia, and thrombocytopenia reported; monitor complete blood cell counts regularly during treatment

                    Atrial fibrillation and atrial flutter occurred; monitor for signs and symptoms of arrhythmias (eg, palpitations, dizziness, syncope, dyspnea) and manage appropriately

                    Second primary malignancies, including non-skin carcinomas, developed; advise patients to use sun protection and monitor for development of second primary malignancies

                    Based on findings in animals, fetal harm may occur when administered to pregnant females

                    Infections

                    • Serious and fatal infections (eg, bacterial, viral, or fungal) and opportunistic infection reported
                    • Consider antimicrobial prophylaxis and vaccinations in patients who are at increased risk for infections
                    • Monitor for signs and symptoms of infection, evaluate promptly, and treat appropriately

                    Hemorrhage

                    • Serious and fatal hemorrhage occurred
                    • Major hemorrhage occurred at a higher incidence in patients taking pirtobrutinib without antithrombotic agents than in those taking pirtobrutinib with antithrombotic agents (1.7% vs 0.7%)
                    • Consider the risks and benefits of antithrombotic agents when coadministered with pirtobrutinib
                    • Monitor for signs of bleeding
                    • Consider the benefit-risk of withholding pirtobrutinib for 3-7 days pre- and post-surgery depending upon type of surgery and risk of bleeding

                    Drug interaction overview

                    • CYP3A4 substrate
                    • P-gp inhibitor
                    • Moderate CYP2C8 and BCRP inhibitor
                    • Weak CYP2C19 and CYP3A inhibitor
                    • Strong CYP3A inhibitors
                      • Avoid coadministration; if unavoidable, reduce pirtobrutinib dose
                      • Strong CYP3A inhibitors increase pirtobrutinib systemic exposure and risk for adverse reactions
                    • Strong or moderate CYP3A inducers
                      • Avoid coadministration
                      • If use of moderate CYP3A inducers is unavoidable, increase pirtobrutinib dose
                      • Strong or moderate CYP3A inducers decrease pirtobrutinib systemic exposure and may reduce pirtobrutinib efficacy
                    • Sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP substrates
                      • Pirtobrutinib may increase plasma concentrations of sensitive P-gp, CYP2C8, BCRP, which may increase the risk of adverse reactions related to these substrates
                      • Refer to prescribing information for sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP substrates for dosing recommendations
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                    Pregnancy & Lactation

                    Pregnancy

                    Based on findings from animal studies, fetal harm may cause when administered to pregnant females

                    No data are available on use in pregnant females to evaluate for a drug-associated risk

                    Verify pregnancy status in females of reproductive potential before initiating

                    Contraception

                    • Females of reproductive potential: Use effective contraception during treatment and for 1 week after last dose

                    Animal data

                    • Doses ≥375 mg/kg BID caused decreased fetal body weights and increased incidence of malformations and variations in urinary tract (including absent or abnormal ureters and kidneys), reproductive tract (mispositioned ovaries and misshapen uterus), and bone (misshapen sternebrae)
                    • At 500 mg/kg BID, total resorption observed
                    • At 375 mg/kg BID in rats, maternal systemic exposures (AUC) were ~3 times the human exposure at 200 mg qDay
                    • Advise pregnant females of potential risk to a fetus

                    Lactation

                    There are no data on drug presence in human milk or the effects on breastfed children or milk production

                    Advise females not to breastfeed during treatment and for 1 week after last dose

                    Pregnancy Categories

                    A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

                    B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

                    C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

                    D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

                    X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

                    NA: Information not available.

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                    Pharmacology

                    Mechanism of Action

                    Bruton tyrosine kinase (BTK) inhibitor

                    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 the C481 mutation, ultimately inhibiting BTK kinase activity

                    Absorption

                    Peak plasma concentration (Cmax): 3,670 ng/mL (Cycle 1 Day 8); 6,460 ng/mL (steady-state)

                    Median peak plasma time (tmax): 2 hr

                    AUC: 81,800 h⋅ng/mL (Cycle 1 Day 8); 91,300 h⋅ng/mL (steady-state)

                    Steady-state achieved at 5 days

                    Accumulation ratio: 1.63

                    Bioavailability: 85.5%

                    Effects of food

                    • High-fat meal: Decreased Cmax by 23% and delayed tmax by 1 hr

                    Distribution

                    Vd: 32.8 L

                    Protein bound: 96%

                    Mean blood-to-plasma ratio: 0.79

                    Metabolism

                    Primarily metabolized by CYP3A4 and direct glucuronidation by UGT1A8 and UGT1A9

                    Elimination

                    Half-life: ~19 hr

                    Clearance: 2.02 L/hr

                    Excretion: Feces (37% [18% unchanged]); urine (57% [10% unchanged]

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                    Administration

                    Oral Administration

                    Take with or without food at the same time each day

                    Swallow tablets whole with water; do NOT cut, crush, or chew

                    Missed dose

                    • Missed dose >12 hr: Do not make up dose and take next dose as scheduled

                    Storage

                    Tablets: Store at room temperature 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

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                    Patient Handout

                    A Patient Handout is not currently available for this monograph.
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                    Formulary

                    FormularyPatient Discounts

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                    The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

                    Tier Description
                    1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                    2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                    3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                    4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    NC NOT COVERED – Drugs that are not covered by the plan.
                    Code Definition
                    PA Prior Authorization
                    Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
                    QL Quantity Limits
                    Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
                    ST Step Therapy
                    Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
                    OR Other Restrictions
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                    Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.