Imbruvica Tablets

— THERAPEUTIC DISORDERS TREATED —
  • Leukemias, lymphomas, and other hematologic cancers
  • Miscellaneous immune disorders
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Imbruvica Tablets Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Ibrutinib 140mg, 280mg, 420mg, 560mg.

    Pharmacological Class

    Bruton tyrosine kinase (BTK) inhibitor.

    See Also

    How Supplied

    Caps 70mg—28; 140mg—90, 120; Tabs—28 (2×14 blister cards)

    How Supplied

    Tablets—28 (2×14 blister cards)

    • 140mg: yellow green  to green round tablets; debossed with “ibr” on one side and “140” on the other side
    • 280mg: purple oblong tablets; debossed with “ibr” on one side and “280” on the other side
    • 420mg: yellow green to green oblong tablets; debossed with “ibr” on one side and “420” on the other side
    • 560mg: yellow to orange oblong tablets; debossed with “ibr” on one side and “560” on the other side

    Storage

    Store at room temperature 20°C to 25°C (68°F to 77°F). Brief exposure to 15°C to 30°C (59°F to 86°F) permitted.

    Manufacturer

    Pharmacyclics and Janssen Biotech

    Generic Availability

    NO

    Imbruvica Tablets Indications

    Indications

    Mantle cell lymphoma (MCL) in patients who have received at least one prior therapy. Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). CLL/SLL in patients with 17p deletion. Waldenstrom's macroglobulinemia (WM). Marginal zone lymphoma (MZL) in patients who require systemic treatment and have received at least one prior anti-CD20-based therapy.

    Imbruvica Tablets Dosage and Administration

    Prior to Treatment Evaluations

    Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function.

    Verify pregnancy status prior to initiating treatment.

     

    Adult

    Swallow whole with water. Take at same time each day. MCL and MZL: 560mg once daily. CLL/SLL (with or without bendamustine/rituximab, obinutuzumab, or rituximab) and WM (with or without rituximab): 420mg once daily. Combination therapy: consider giving ibrutinib prior to rituximab or obinutuzumab when given on same day. All: treat until disease progression or unacceptable toxicity. Hepatic impairment (mild): 140mg once daily; (moderate): 70mg once daily; (severe): avoid. Dose modifications for toxicities or concomitant CYP3A inhibitors (eg, voriconazole, posaconazole): see full labeling.

    Children

    Not established.

    Renal Impairment

    Mild or moderate renal impairment: no influence on the exposure of ibrutinib

    Severe renal impairment: no data available

    Hepatic Impairment

    See Dosing and Administration.

    Mild or moderate hepatic impairment: reduce dose; monitor more frequently

    Severe hepatic impairment: avoid use

    Study data showed that the AUC and Cmax of ibrutinib increased 2.7-fold and 5.2-fold in patients with mild hepatic impairment, 8.2-fold and 8.8-fold in patients with moderate hepatic impairment and 9.8-fold and 7-fold in patients with severe hepatic impairment relative to patients with normal liver function.

    Other Modifications

    Females of reproductive potential: use effective contraception during treatment and for 1 month after the last dose. Verify pregnancy status prior to initiating treatment.

    Males with female partners of reproductive age: use effective contraception during treatment and for 1 month after the last dose.

    Plasmapheresis: Management of hyperviscosity in WM patients may include plasmapheresis before and during treatment with Imbruvica. Modifications to dosing are not required.

    Imbruvica Tablets Contraindications

    Not Applicable

    Imbruvica Tablets Boxed Warnings

    Not Applicable

    Imbruvica Tablets Warnings/Precautions

    Warnings/Precautions

    Risk of serious hemorrhagic events; consider the benefit/risk of withholding treatment for 3–7 days pre-and post-surgery. Monitor for fever and infections; evaluate promptly if occurs. Consider prophylaxis for opportunistic infections in high risk patients. Monitor for cytopenias; obtain CBCs monthly. Monitor for cardiac arrhythmias and cardiac function at baseline then periodically (esp. in those with cardiac risk factors, hypertension, diabetes, acute infections, history of cardiac arrhythmias); do ECG if arrhythmic symptoms, new onset dyspnea, or other cardiovascular concerns develop. Monitor for hypertension; initiate or adjust anti-hypertensives as appropriate. Risk of second primary malignancies (eg, non-melanoma skin cancer, others). Monitor for tumor lysis syndrome in patients at risk (eg, high tumor burden). Hepatic impairment (see Adult). Maintain adequate hydration. Embryo-fetal toxicity. Advise females of reproductive potential and males (w. female partners) to use effective contraception during and for 1 month after the last dose. Pregnancy: exclude status prior to initiation. Nursing mothers: not recommended (during and for 1 week after the last dose).

    Warnings/Precautions

    Hemorrhage

    • Fatal bleeding events have occurred in patients receiving Imbruvica; the mechanism of bleeding events is not well understood.
    • Use of anticoagulant/antiplatelet agents concomitantly increases the risk of major hemorrhage; consider the risks/benefits of concomitant anticoagulant/antiplatelet therapy.
    • Monitor for signs/symptoms of bleeding.
    • Consider the benefit-risk of withholding Imbruvica for at least 3-7 days pre- and post-surgery depending on the type of surgery and the risk of bleeding.

    Infections

    • Bacterial, viral and fungal infections have occurred with Imbruvica therapy.
    • Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have been reported.
    • In patients at risk of opportunistic infections: consider prophylaxis according to standard of care.
    • Monitor and evaluate patients for fever and infections and treat appropriately.

    Cardiac Arrhythmias, Cardiac Failure, and Sudden Death

    • Fatal and serious cardiac arrhythmias and cardiac failure have occurred with Imbruvica.
    • Patients with cardiac abnormalities may be at greater risk.
    • Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function.
    • For patients who develop symptoms of arrhythmia, new onset dyspnea, or other cardiovascular concerns: obtain further evaluation (eg, ECG, echocardiogram) as indicated.
    • Manage cardiac arrhythmias and cardiac failure appropriately; refer to dose modification guidelines and consider the benefits/risks of continued treatment.

    Hypertension

    • Median time to onset of hypertension was observed to be 5.9 months (range, 0.03 to 24 months).
    • Monitor BP, initiate or adjust antihypertensive medication throughout treatment with Imbruvica.
    • Follow dosage modification guidelines for grade 3 or higher hypertension.

    Cytopenias

    • Neutropenia, thrombocytopenia, and anemia reported in clinical trials.
    • Monitor CBC monthly.

    Second Primary Malignancies

    • Other malignancies, including non-skin carcinomas, occurred among patients who received Imbruvica in clinical trials.
    • The most frequent second primary malignancy was non-melanoma skin cancer.

    Tumor Lysis Syndrome

    • Infrequently reported with Imbruvica.
    • Assess baseline risk and take appropriate precautions.
    • Monitor closely and treat as appropriate.

    Pregnancy Considerations

    Can cause fetal harm when administered to a pregnant woman. Verify pregnancy status prior to initiating treatment.

    Nursing Mother Considerations

    There is no information regarding the presence of ibrutinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Women should not breastfeed during treatment and for 1 week after the last dose.

    Pediatric Considerations

    Mature B-cell Non-Hodgkin Lymphoma

    Safety and effectiveness of Imbruvica in combination with chemoimmunotherapy were assessed but have not been established based on an open-label, randomized study in 35 patients, which included 26 pediatric patients (5 to <17 years old) with previously treated mature B-cell nonHodgkin lymphoma. The study was stopped for futility.

    MCL, CLL/SLL, CLL/SLL with 17p deletion, WM, MZL

    Safety and effectiveness of Imbruvica in pediatric patients have not been established.

    Geriatric Considerations

    No overall differences in effectiveness were observed between younger and older patients. Anemia, pneumonia, thrombocytopenia, hypertension, and atrial fibrillation occurred more frequently among older patients treated with Imbruvica.

    Renal Impairment Considerations

    Mild or moderate renal impairment: no influence on the exposure of ibrutinib

    Severe renal impairment: no data available

    Hepatic Impairment Considerations

    See Dosing and Administration.

    Mild or moderate hepatic impairment: reduce dose; monitor more frequently

    Severe hepatic impairment: avoid use

    Study data showed that the AUC and Cmax of ibrutinib increased 2.7-fold and 5.2-fold in patients with mild hepatic impairment, 8.2-fold and 8.8-fold in patients with moderate hepatic impairment and 9.8-fold and 7-fold in patients with severe hepatic impairment relative to patients with normal liver function.

    Other Considerations for Specific Populations

    Females of reproductive potential: use effective contraception during treatment and for 1 month after the last dose. Verify pregnancy status prior to initiating treatment.

    Males with female partners of reproductive age: use effective contraception during treatment and for 1 month after the last dose.

    Plasmapheresis: Management of hyperviscosity in WM patients may include plasmapheresis before and during treatment with Imbruvica. Modifications to dosing are not required.

    Imbruvica Tablets Pharmacokinetics

    Absorption

    Ibrutinib is absorbed after oral administration with a median Tmax of 1 hour to 2 hours.

    Distribution

    Reversible binding of ibrutinib to human plasma protein in vitro was 97.3%

    Metabolism

    Ibrutinib is metabolized to several metabolites primarily by cytochrome P450 (CYP)3A and to a minor extent by CYP2D6.

    Elimination

    The half-life of ibrutinib is 4 hours to 6 hours. Eliminated primarily via feces.

    Imbruvica Tablets Interactions

    Interactions

    Avoid concomitant strong CYP3A inhibitors (eg, ketoconazole); if short-term use (eg, anti-infectives for ≤7days), interrupt ibrutinib therapy. Concomitant posaconazole, voriconazole, and moderate CYP3A inhibitors (eg, erythromycin): adjust ibrutinib dose (see full labeling). Avoid grapefruit and Seville oranges during treatment. Avoid concomitant strong CYP3A inducers (eg, rifampin). Increased risk of hemorrhage with concomitant antiplatelets or anticoagulants; monitor.

    Imbruvica Tablets Adverse Reactions

    Adverse Reactions

    Thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, muscle spasms, stomatitis, nausea, hemorrhage, pneumonia, pyrexia, stomatitis, abdominal pain, headache.

    Imbruvica Tablets Clinical Trials

    Clinical Trials

    Mantle Cell Lymphoma

    The safety and efficacy of Imbruvica in patients with MCL who have received at least 1 prior therapy were evaluated in Study 1104 (ClinicalTrials.gov Identifier: NCT01236391), an open-label, multi-center, single-arm trial of 111 previously treated patients. The primary endpoint was investigator-assessed overall response rate (ORR).

    Findings showed an ORR of 65.8% (95% CI, 56.2-74.5), with 17.1% of patients having a complete response and 48.6% of patients having a partial response. Median duration of response (DoR) was 17.5 months (95% CI, 15.8-NE). Median time to response was 1.9 months.

    Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

    The safety and efficacy of IMBRUVICA in patients with CLL/SLL were demonstrated in 1 uncontrolled trial and 5 randomized, controlled trials.

    Study 1102 (ClinicalTrials.gov Identifier: NCT01105247)

    • Open-label, multicenter trial conducted in 48 previously treated CLL patients.
    • Imbruvica was administered orally at 420mg once daily until disease progression or unacceptable toxicity.
    • The ORR was 58.3% (95% CI, 43.2-72.4), all partial responses. 
    • None of the patients achieved a complete response.
    • The DoR ranged from 5.6 to 24.2+ months; median DoR was not reached.

    RESONATE (ClinicalTrials.gov Identifier: NCT01578707)

    • Randomized, multicenter, open-label, phase 3 study of Imbruvica vs ofatumumab conducted in 391 patients with previously treated CLL or SLL.
    • Compared with ofatumumab, Imbruvica significantly improved progression free survival (PFS; hazard ratio [HR] for progression or death, 0.22 [95% CI, 0.15-0.32]; P <.001) and overall survival (OS; HR for death, 0.43 [95% CI, 0.24-0.79]; P =.005).
    • 63 month follow-up: median PFS was 44.1 months for Imbruvica and 8.1 months for ofatumumab; ORR was 87.2% and 22.4%, respectively.
    • Similar effects seen in patients with del 17p CLL/SLL.

    RESONATE-2 (ClinicalTrials.gov Identifier: (NCT01722487)

    • Randomized, multicenter, open-label, phase 3 study of Imbruvica vs chlorambucil conducted in 269 patients with treatment naïve CLL or SLL who were 65 years of age or older. 
    • Imbruvica significantly prolonged PFS by reducing the risk of progression or death by 84% vs chlorambucil (hazard ratio [HR] 0.16, 95% CI, 0.09-0.28). 
    • Imbruvica was also associated with a significantly higher ORR (82.4%) vs chlorambucil (35.3%). 
    • A total of 5 patients achieved a complete response in the Imbruvica arm vs 2 patients in the chlorambucil arm.
    • 55 month follow-up: median PFS was not reached in the Imbruvica arm.

    HELIOS (ClinicalTrials.gov Identifier: NCT01611090)

    • Randomized, multicenter, double-blind, phase 3 trial that evaluated Imbruvica in combination with bendamustine and rituximab (BR) vs placebo plus BR in relapsed/refractory patients with CLL/SLL (N=578).
    • Imbruvica plus BR demonstrated an 80% reduction in the risk of progression or death (HR, 0.20, 95% CI, 0.15-0.28) vs placebo plus BR.
    • ORR was 82.7% for Imbruvica plus BR and 67.8% for placebo plus BR.

    iLLUMINATE (ClinicalTrials.gov Identifier: NCT02264574)

    • Randomized, multicenter, phase 3 study of Imbruvica in combination with obinutuzumab vs chlorambucil in combination with obinutuzumab conducted in patients with treatment naïve CLL or SLL (N=229).
    • Treatment with Imbruvica + obinutuzumab led to a significant improvement in PFS vs chlorambucil + obinutuzumab after a median follow-up of 31 months (median not evaluable [NE] vs 19 months; hazard ratio [HR] 0.23, 95% CI, 0.15-0.37; P <.0001).
    • For patients with high-risk disease (17p deletion/TP53 mutation, 11q deletion, or unmutated IGHV), the PFS HR was 0.15 (95% CI, 0.09-0.27).  
    • ORR was 88.5% in the Imbruvica arm vs 73.3% in the chlorambucil arm.

    E1912 (ClinicalTrials.gov Identifier: NCT02048813)

    • Randomized, multicenter, phase 3 study of Imbruvica in combination with rituximab vs standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy conducted in adult patients who were 70 years or younger with previously untreated CLL or SLL requiring systemic therapy.
    • At 37 months, treatment with Imbruvica plus rituximab was associated with a statistically significant improvement in PFS when compared with the FCR arm (HR 0.34; 95% CI, 0.22-0.52; P <.0001). 
    • 49 month follow-up: median OS was not reached with a total of 23 deaths; 11 (3%) in the Imbruvica plus rituximab and 12 (7%) in the FCR treatment arms.

    Waldenström’s Macroglobulinemia

    The safety and efficacy of Imbruvica in patients with WM were demonstrated in 2 single-arm trials and 1 randomized, controlled trial.

    Study 1118  (ClinicalTrials.gov Identifier: NCT01614821) 

    • Open-label, multicenter, single-arm trial conducted in 63 previously treated patients with WM.
    • Imbruvica was administered orally at 420mg once daily until disease progression or unacceptable toxicity.
    • Response rate was 61.9% (95% CI, 48.8-73.9): 0 with complete response (CR), 11.1% with very good partial response (VGPR), 50.8% with partial response (PR).
    • Median DoR: NE (2.8+, 18.8+).
    • Median time to response was 1.2 months (range, 0.7-13.4 months).

    INNOVATE Monotherapy Arm

    • 31 patients with previously treated WM who failed prior rituximab-containing therapy and received single-agent Imbruvica.
    • 61 month follow-up: response rate was 77% (0% CR, 29% VGPR, 48% PR).
    • Median DoR: 33 months (range, 2.4 to 60.2+ months).

    INNOVATE (ClinicalTrials.gov Identifier: NCT02165397)

    • Randomized, double-blind, placebo-controlled, phase 3 study of Imbruvica or placebo in combination with rituximab conducted in treatment naïve or previously treated patients with WM (N=150).
    • At 63 months, patients treated with Imbruvica + rituximab experienced an 75% reduction in relative risk of disease progression or death compared with those treated with placebo + rituximab (hazard ratio 0.25 [95% CI, 0.15-0.42); P <.0001). 
    • Rate of response was greater in the Imbruvica + rituximab group compared with placebo + rituximab (76% vs 31%, respectively; P <.0001).

    Marginal Zone Lymphoma

    The safety and efficacy of Imbruvica in MZL were evaluated in Study 1121 (ClinicalTrials.gov Identifier: NCT01980628), an open-label, multicenter, single-arm trial of patients who received at least 1 prior therapy (N=63). In these patients, ORR was 46% (95% CI, 33.4-59.1) with 3.2% of patients achieving CR and 42.9% achieving PR. Median time to response was 4.5 months (range, 2.3 to 16.4 months). Overall response rates were 46.9%, 41.2%, and 50.0% for the 3 MZL subtypes (MALT, nodal, splenic), respectively.

    Imbruvica Tablets Note

    Not Applicable

    Imbruvica Tablets Patient Counseling

    Patient Counseling

    Imbruvica (capsules and tablets) should be swallowed whole. The medication should be taken at approximately the same time each day. Take a missed dose as soon as possible on the same day and return to normal schedule the following day; do not take extra doses to make up for the missed dose.

    Inform patients of common side effects as well as potentially serious adverse events: hemorrhage; infections; cardiac arrhythmias, cardiac failure and sudden death; hypertension, secondary primary malignancies, tumor lysis syndrome, embryo-fetal toxicity.

    Use effective contraception during treatment and for 1 month after the last dose.

    Avoid breastfeeding during treatment and for 1 week after the last dose.

    Patients may experience loose stools or diarrhea; maintain adequate hydration. Report persistent diarrhea.

    Cost Savings Program

    Imbruvica By Your Side Patient Support Program

    Imbruvica Tablets Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Ibrutinib 140mg, 280mg, 420mg, 560mg.

    Pharmacological Class

    Bruton tyrosine kinase (BTK) inhibitor.

    See Also

    How Supplied

    Caps 70mg—28; 140mg—90, 120; Tabs—28 (2×14 blister cards); Oral susp—108mL

    How Supplied

    Tablets—28 (2×14 blister cards)

    • 140mg: yellow green  to green round tablets; debossed with “ibr” on one side and “140” on the other side
    • 280mg: purple oblong tablets; debossed with “ibr” on one side and “280” on the other side
    • 420mg: yellow green to green oblong tablets; debossed with “ibr” on one side and “420” on the other side
    • 560mg: yellow to orange oblong tablets; debossed with “ibr” on one side and “560” on the other side

    Storage

    Store at room temperature 20°C to 25°C (68°F to 77°F). Brief exposure to 15°C to 30°C (59°F to 86°F) permitted.

    Manufacturer

    Pharmacyclics and Janssen Biotech

    Generic Availability

    NO

    Imbruvica Tablets Indications

    Indications

    Chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.

    Imbruvica Tablets Dosage and Administration

    Prior to Treatment Evaluations

    Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function.

    Verify pregnancy status prior to initiating treatment.

     

    Adult

    Swallow caps/tabs whole with water. Take at same time each day. ≥12yrs: 420mg once daily. Treat until disease progression, recurrence of an underlying malignancy, or unacceptable toxicity; discontinue when treatment for cGVHD no longer required. Hepatic impairment (total bilirubin level >1.5–3×ULN [unless of non-hepatic origin or due to Gilbert’s syndrome]): 140mg once daily; (total bilirubin level >3×ULN [unless of non-hepatic origin or due to Gilbert’s syndrome]): avoid. Dose modifications for toxicities or concomitant CYP3A inhibitors (eg, voriconazole, posaconazole): see full labeling.

    Children

    <1yr: not established. Can use caps/tabs or oral susp. Swallow caps/tabs whole with water. Take at same time each day. 1–<12yrs: 240mg/m2 once daily (based on BSA); max: up to 420mg once daily. Treat until disease progression, recurrence of an underlying malignancy, or unacceptable toxicity; discontinue when treatment for cGVHD no longer required. Hepatic impairment (total bilirubin level >1.5–3×ULN [unless of non-hepatic origin or due to Gilbert’s syndrome]): 80mg/m2 once daily; (total bilirubin level >3×ULN [unless of non-hepatic origin or due to Gilbert’s syndrome]): avoid. Recommended dose based on BSA, dose modifications for toxicities or concomitant CYP3A inhibitors (eg, voriconazole, posaconazole): see full labeling.

    Renal Impairment

    Mild or moderate renal impairment: no influence on the exposure of ibrutinib

    Severe renal impairment: no data available

    Hepatic Impairment

    See Dosing and Administration.

    Total bilirubin level >1.5 to 3x upper limit of normal (ULN) (unless of nonhepatic origin or due to Gilbert syndrome): reduce dose

    Total bilirubin level >3x ULN (unless of nonhepatic origin or due to Gilbert syndrome): avoid use

    Other Modifications

    Females of reproductive potential: use effective contraception during treatment and for 1 month after the last dose. Verify pregnancy status prior to initiating treatment.

    Males with female partners of reproductive age: use effective contraception during treatment and for 1 month after the last dose.

    Imbruvica Tablets Contraindications

    Not Applicable

    Imbruvica Tablets Boxed Warnings

    Not Applicable

    Imbruvica Tablets Warnings/Precautions

    Warnings/Precautions

    Risk of serious hemorrhagic events; consider the benefit/risk of withholding treatment for 3–7 days pre-and post-surgery. Monitor for fever and infections; evaluate promptly if occurs. Consider prophylaxis for opportunistic infections in high risk patients. Monitor for cytopenias; obtain CBCs monthly. Monitor for cardiac arrhythmias and cardiac function at baseline then periodically (esp. in those with cardiac risk factors, hypertension, diabetes, acute infections, history of cardiac arrhythmias); do ECG if arrhythmic symptoms, new onset dyspnea, or other cardiovascular concerns develop. Monitor for hypertension; initiate or adjust anti-hypertensives as appropriate. Risk of second primary malignancies (eg, non-melanoma skin cancer, others). Monitor for tumor lysis syndrome in patients at risk (eg, high tumor burden). Hepatic impairment (see Adult). Maintain adequate hydration. Embryo-fetal toxicity. Advise females of reproductive potential and males (w. female partners) to use effective contraception during and for 1 month after the last dose. Pregnancy: exclude status prior to initiation. Nursing mothers: not recommended (during and for 1 week after the last dose).

    Warnings/Precautions

    Hemorrhage

    • Fatal bleeding events have occurred in patients receiving Imbruvica; the mechanism of bleeding events is not well understood.
    • Use of anticoagulant/antiplatelet agents concomitantly increases the risk of major hemorrhage; consider the risks/benefits of concomitant anticoagulant/antiplatelet therapy.
    • Monitor for signs/symptoms of bleeding.
    • Consider the benefit-risk of withholding Imbruvica for at least 3-7 days pre- and post-surgery depending on the type of surgery and the risk of bleeding.

    Infections

    • Bacterial, viral and fungal infections have occurred with Imbruvica therapy.
    • Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have been reported.
    • In patients at risk of opportunistic infections: consider prophylaxis according to standard of care.
    • Monitor and evaluate patients for fever and infections and treat appropriately.

    Cardiac Arrhythmias, Cardiac Failure, and Sudden Death

    • Fatal and serious cardiac arrhythmias and cardiac failure have occurred with Imbruvica.
    • Patients with cardiac abnormalities may be at greater risk.
    • Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function.
    • For patients who develop symptoms of arrhythmia, new onset dyspnea, or other cardiovascular concerns: obtain further evaluation (eg, ECG, echocardiogram) as indicated.
    • Manage cardiac arrhythmias and cardiac failure appropriately; refer to dose modification guidelines and consider the benefits/risks of continued treatment.

    Hypertension

    • Median time to onset of hypertension was observed to be 5.9 months (range, 0.03 to 24 months).
    • Monitor BP, initiate or adjust antihypertensive medication throughout treatment with Imbruvica.
    • Follow dosage modification guidelines for grade 3 or higher hypertension.

    Cytopenias

    • Neutropenia, thrombocytopenia, and anemia reported in clinical trials.
    • Monitor CBC monthly.

    Second Primary Malignancies

    • Other malignancies, including non-skin carcinomas, occurred among patients who received Imbruvica in clinical trials.
    • The most frequent second primary malignancy was non-melanoma skin cancer.

    Tumor Lysis Syndrome

    • Infrequently reported with Imbruvica.
    • Assess baseline risk and take appropriate precautions.
    • Monitor closely and treat as appropriate.

    Pregnancy Considerations

    Can cause fetal harm when administered to a pregnant woman. Verify pregnancy status prior to initiating treatment.

    Nursing Mother Considerations

    There is no information regarding the presence of ibrutinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Women should not breastfeed during treatment and for 1 week after the last dose.

    Pediatric Considerations

    Safety and effectiveness of Imbruvica have been established for treatment of cGVHD after failure of 1 or more lines of systemic therapy in pediatric patients 1 year of age and older. Use for this indication is supported by evidence from the iMAGINE study.

    Safety and effectiveness have not been established for this indication in pediatric patients less than 1 year of age.

    Geriatric Considerations

    No overall differences in effectiveness were observed between younger and older patients. Anemia, pneumonia, thrombocytopenia, hypertension, and atrial fibrillation occurred more frequently among older patients treated with Imbruvica.

    Renal Impairment Considerations

    Mild or moderate renal impairment: no influence on the exposure of ibrutinib

    Severe renal impairment: no data available

    Hepatic Impairment Considerations

    See Dosing and Administration.

    Total bilirubin level >1.5 to 3x upper limit of normal (ULN) (unless of nonhepatic origin or due to Gilbert syndrome): reduce dose

    Total bilirubin level >3x ULN (unless of nonhepatic origin or due to Gilbert syndrome): avoid use

    Other Considerations for Specific Populations

    Females of reproductive potential: use effective contraception during treatment and for 1 month after the last dose. Verify pregnancy status prior to initiating treatment.

    Males with female partners of reproductive age: use effective contraception during treatment and for 1 month after the last dose.

    Imbruvica Tablets Pharmacokinetics

    Absorption

    Ibrutinib is absorbed after oral administration with a median Tmax of 1 hour to 2 hours.

    Distribution

    Reversible binding of ibrutinib to human plasma protein in vitro was 97.3%

    Metabolism

    Ibrutinib is metabolized to several metabolites primarily by cytochrome P450 (CYP)3A and to a minor extent by CYP2D6.

    Elimination

    The half-life of ibrutinib is 4 hours to 6 hours. Eliminated primarily via feces.

    Imbruvica Tablets Interactions

    Interactions

    Avoid concomitant strong CYP3A inhibitors (eg, ketoconazole); if short-term use (eg, anti-infectives for ≤7days), interrupt ibrutinib therapy. Concomitant posaconazole, voriconazole, and moderate CYP3A inhibitors (eg, erythromycin): adjust ibrutinib dose (see full labeling). Avoid grapefruit and Seville oranges during treatment. Avoid concomitant strong CYP3A inducers (eg, rifampin). Increased risk of hemorrhage with concomitant antiplatelets or anticoagulants; monitor.

    Imbruvica Tablets Adverse Reactions

    Adverse Reactions

    Thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, muscle spasms, stomatitis, nausea, hemorrhage, pneumonia, pyrexia, stomatitis, abdominal pain, headache.

    Imbruvica Tablets Clinical Trials

    Clinical Trials

    Study 1129 (ClinicalTrials.gov Identifier: NCT02195869)

    • The safety and efficacy of Imbruvica in cGVHD were evaluated in an open-label, multicenter, single-arm trial of 42 patients with cGVHD after failure of first line corticosteroid therapy and requiring additional therapy.
    • After receiving Imbruvica 420mg once daily, the overall response rate (ORR) was reported to be 67% (95% CI, 51-80). 
    • Median time to best response coinciding with the first scheduled response assessment was 12.3 weeks. 
    • Patient response was seen for all organs involved with cGVHD, including the skin, mouth, liver, and gastrointestinal tract. 
    • Nearly half of the patients (48%) had responses lasting ≥5 months.

    iMAGINE (ClinicalTrials.gov Identifier: NCT03790332)

    • The safety and efficacy of Imbruvica were evaluated in an open-label, multicenter, single-arm trial for the treatment of pediatric and young adult patients age 1 year to less than 22 years with moderate or severe cGVHD.
    • Results showed an ORR (main efficacy outcome measure) of 60% (n=28; 95% CI, 44-74) through week 25, of which 4% (n=2) of patients achieved CR and 55% (n=26) achieved PR. 
    • Median duration of response was 5.3 months (95% CI, 2.8-8.8).  
    • Median time to first response was 0.9 month (range, 0.9-6.1 months), and the median time from first response to death or new systemic therapies for cGVHD was 14.8 months (95% CI, 4.6-not evaluable).
    • 50% of patients 12 years of age and older showed at least a 7-point decrease in patient-reported symptom bother through week 25, as assessed by the Lee Symptom Scale overall summary score.

    Imbruvica Tablets Note

    Not Applicable

    Imbruvica Tablets Patient Counseling

    Patient Counseling

    Imbruvica (capsules and tablets) should be swallowed whole. The medication should be taken at approximately the same time each day. Take a missed dose as soon as possible on the same day and return to normal schedule the following day; do not take extra doses to make up for the missed dose.

    Inform patients of common side effects as well as potentially serious adverse events: hemorrhage; infections; cardiac arrhythmias, cardiac failure and sudden death; hypertension, secondary primary malignancies, tumor lysis syndrome, embryo-fetal toxicity.

    Use effective contraception during treatment and for 1 month after the last dose.

    Avoid breastfeeding during treatment and for 1 week after the last dose.

    Patients may experience loose stools or diarrhea; maintain adequate hydration. Report persistent diarrhea.

    Cost Savings Program

    Imbruvica By Your Side Patient Support Program

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