zanubrutinib (Rx)

Brand and Other Names:Brukinsa
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Dosing & Uses

AdultPediatric

capsules

  • 80mg

Mantel Cell Lymphoma

Indicated for mantle cell lymphoma (MCL) in patients who received at least 1 prior therapy

160 mg PO BID or 320 mg PO qDay until disease progression or unacceptable toxicity

Dosage Modifications

Adverse reactions associated with therapy

  • Grade ≥3 nonhematological toxicities
  • Grade 3 febrile neutropenia
  • Grade 3 thrombocytopenia with significant bleeding
  • Grade 4 neutropenia (lasting >10 consecutive days)
  • Grade 4 thrombocytopenia (lasting >10 consecutive days)
  • Do not regard asymptomatic lymphocytosis as an adverse reaction; these patients should continue therapy

Dosage modifications based on number of occurrences

  • First: Interrupt therapy; once resolved to recovery to Grade ≤1 or baseline, resume at 160 mg BID or 320 mg qDay
  • Second: Interrupt therapy; once resolved to recovery to Grade ≤1 or baseline, resume at 80 mg BID or 160 mg qDay
  • Third: Interrupt therapy; once resolved to recovery to Grade ≤1 or baseline, resume at 80 mg qDay
  • Fourth: Discontinue therapy

Coadministration with CYP3A inhibitors or inducers

  • Strong CYP3A inhibitor: 80 mg PO qDay; interrupt dose as recommended for adverse reactions
  • Moderate CYP3A inhibitor: 80 mg PO BID; interrupt dose as recommended for adverse reactions
  • Moderate or strong CYP3A inducer: Avoid concomitant use
  • After discontinuation of CYP3A4 inhibitor, resume previous dose of zanubrutinib

Renal impairment

  • Mild-to-moderate (eCrCl ≥ 30 mL/min): No dosage adjustment necessary
  • Severe (eCrCl <30 mL/min) or on dialysis: Pharmacokinetics of zanubrutinib is unknown; monitor for adverse effects

Hepatic impairment

  • Mild-to-moderate (Child-Pugh A or B): No dosage modification recommended
  • Severe (Child-Pugh C): 80 mg PO BID

Safety and efficacy not established

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Interactions

Interaction Checker

and zanubrutinib

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            All grades

            • Upper respiratory tract infection (39%)
            • Neutropenia and neutrophil decreased (38-45%)
            • Lymphocytosis (41%)
            • Thrombocytopenia and platelet count decreased (27-40%)
            • Anemia and hemoglobin decreased (14-27%)
            • Rash (36%)
            • Blood uric acid increased (29%)
            • ALT increased (28%)
            • Leukopenia and WBC count decreased (25%)
            • Bilirubin increased (24%)
            • Diarrhea (23%)
            • Pneumonia (15%)
            • Bruising (14%)
            • Hypokalemia (14%)
            • Constipation (13%)
            • Hypertension (12%)
            • Cough (12%)
            • Hemorrhage (11%)
            • Urinary tract infection (11%)

            Grade ≥3

            • Neutropenia and neutrophil decreased (15-20%)
            • Lymphocytosis (16%)

            1-10%

            Hyperuricemia (6%)

            Headache (4.2%)

            Grade ≥3

            • Pneumonia (10%)
            • Anemia and hemoglobin decreased (6-8%)
            • Thrombocytopenia and platelet count decreased (5-7%)
            • Leukopenia and WBC count decreased (5%)
            • Hypertension (3.4%)
            • Hemorrhage (3.4%)
            • Musculoskeletal pain (3.4%)
            • Blood uric acid increased (2.6%)
            • Hypokalemia (1.7%)

            <1%

            Grade ≥3

            • ALT increased (0.9%)
            • Bilirubin increased (0.9%)
            • Urinary tract infection (0.8%)
            • Diarrhea (0.8%)
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            Warnings

            Contraindications

            None

            Cautions

            Grade 3 or 4 cytopenias (eg, neutropenia, thrombocytopenia, anemia) reported; monitor CBC counts during treatment and treat using growth factors or transfusions, as needed

            Second primary malignancies, including nonskin carcinoma, may occur; the most frequent second primary malignancy was skin cancer (basal cell carcinoma and squamous cell carcinoma of skin); advise to use sun protection

            Atrial fibrillation and atrial flutter reported; patients with cardiac risk factors, hypertension, and acute infections may be at increased risk; grade ≥3 events reported with monotherapy; monitor for signs and symptoms of atrial fibrillation and atrial flutter and manage as appropriate

            Infections

            • Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections reported; infections due to hepatitis B virus reactivation have occurred
            • Consider prophylaxis for herpes simplex virus, Pneumocystis jiroveci pneumonia, and other infections according to standard of care in patients who are at increased risk for infections
            • Monitor and evaluate for fever or other signs and symptoms of infection and treat appropriately

            Hemorrhage

            • Fatal and serious hemorrhagic events have occurred in patients with hematological malignancies treated with monotherapy
            • Bleeding events reported with and without concomitant antiplatelet or anticoagulation therapy; coadministration with antiplatelet or anticoagulant medications may further increase risk of hemorrhage
            • Monitor for signs and symptoms of bleeding; discontinue therapy if intracranial hemorrhage of any grade occurs; consider benefit-risk of withholding therapy for 3-7 days presurgery and postsurgery depending on type of surgery and risk of bleeding

            Drug interaction overview

            • Moderate and strong CYP3A4 inhibitors
              • Coadministration with a moderate or strong CYP3A inhibitor increases zanubrutinib plasma levels, which may increase the risk of zanubrutinib toxicities
            • Moderate and strong CYP3A4 inducers
              • Coadministration with a moderate or strong CYP3A inhibitor decreases zanubrutinib plasma levels, which may reduce zanubrutinib efficacy
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            Pregnancy & Lactation

            Pregnancy

            There are no available data on use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

            Avoid pregnancy during administration; warn patients of the potential hazard to the fetus if used during pregnancy or if patient becomes pregnant while taking zanubrutinib

            Pregnancy testing is recommended for females of reproductive potential before initiating therapy

            Animal data

            • Based on findings in animals, fetal harm may occur when administered to a pregnant woman; administration to pregnant rats during organogenesis caused embryofetal toxicity, including malformations, at exposures that were 5 times higher than those reported in patients at recommended dose of 160 mg BID

            Contraception

            • Females of reproductive potential: Use effective contraception during treatment and for at least 1 week following the last dose
            • Males: Advise men to avoid fathering a child while receiving zanubrutinib and for at least 1 week following the last dose

            Lactation

            There are no data on presence of drug or its metabolites in human milk, effects on breastfed child, or on milk production

            Owing to the potential for serious adverse reactions from therapy in a breastfed child, advise lactating women not to breastfeed during treatment and for at least 2 weeks following 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 forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK activity

            BTK is a signaling molecule 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; in nonclinical studies, zanubrutinib inhibited malignant B-cell proliferation and reduced tumor growth

            Absorption

            Peak plasma time: 2 hr

            Peak plasma concentration (steady-state): 314 ng/mL (160 mg BID); 543 ng/mL (320 mg BID)

            AUC (steady-state): 2295 ng⋅hr/mL (160 mg BID); 2180 ng⋅hr/mL (320 mg BID)

            Distribution

            Vd (steady-state): 881 L

            Protein bound: ~94%

            Blood-to plasma ratio: 0.7-0.8

            Metabolism

            Metabolized by CYP3A

            Elimination

            Mean half-life: 2-4 hr following a single oral dose of 160 mg or 320 mg

            Oral clearance: 182 L/hr

            Excretion: Feces (~87% [8% unchanged]); urine (8% [<1% unchanged])

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            Administration

            Oral Administration

            May take with or without food

            Swallow capsules whole with water; do not open, break, or chew capsules

            Missed dose: Take as soon as possible on same day; return to normal schedule the following day

            Storage

            Store at 20-25ºC (68-77ºF); excursions permitted 15-30ºC (59-86ºF)

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            Formulary

            FormularyPatient Discounts

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            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.
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            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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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.