Imbruvica Oral Suspension

— THERAPEUTIC CATEGORIES —
  • Miscellaneous immune disorders
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Imbruvica Oral Suspension Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Ibrutinib 70mg/mL; oral susp.

    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

    Oral Suspension—108mL

    • 70mg/mL, white to off-white suspension.
      The oral suspension bottle is provided in a carton with two 3mL reusable oral dosing syringes.

    Storage

    Store bottle at 2°C to 25°C (36°F to 77°F). Do not freeze. Dispense in the original sealed container. Discard any unused Imbruvica oral suspension remaining 60 days after first opening the bottle.

    Manufacturer

    Pharmacyclics and Janssen Biotech

    Generic Availability

    NO

    Imbruvica Oral Suspension Indications

    Indications

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

    Imbruvica Oral Suspension 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

    Use caps or tabs form. Swallow 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.

    Imbruvica Oral Suspension Contraindications

    Not Applicable

    Imbruvica Oral Suspension Boxed Warnings

    Not Applicable

    Imbruvica Oral Suspension 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 Oral Suspension 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 Oral Suspension 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 Oral Suspension 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 Oral Suspension 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 Oral Suspension Note

    Not Applicable

    Imbruvica Oral Suspension Patient Counseling

    Patient Counseling

    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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