IMBRUVICA® (Ibrutinib) 420, 280, 140 mg tablets | 140, 70 mg capsule Logo
IMBRUVICA® (Ibrutinib) 420, 280, 140 mg tablets | 140, 70 mg capsule || 70mg/mL oral suspension Logo
Chronic Lymphocytic Leukemia (Adult Patients) Waldenström's Macroglobulinemia (Adult Patients) Previously Treated Chronic Graft Versus Host Disease (Adult and Pediatric Patients Age 1 Year and Older)

For the first time ever 1

Approved in August 2022

Imbruvica® Safety and effectiveness have been established for children as young as 1 year of age with previously treated cGVHD2*

*This indication is supported by evidence from the iMAGINE study

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cGVHD TREATMENT AVAILABLE AS AN ORAL SUSPENSION FOR CHILDREN

Pediatric patients under the age of 12 with cGVHD and have failed one or more lines of systemic therapy have limited treatment options1

Data from the iMAGINE trial support that IMBRUVICA® produced a clinically meaningful response in pediatric patients with previously treated cGVHD2

cGVHD

Indication2

IMBRUVICA® is indicated for the treatment of adult and pediatric patients age 1 year and older with chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy.

Study design: iMAGINE trial2,3

An open-label, multicenter, single-arm, phase 1/2 study consisting of 47 patients aged 1 to <22 years with previously treated moderate or severe cGVHD.

Select Inclusion Criteria

  • Platelets ≥30 × 109/L and no transfusion for 7 days
  • Absolute neutrophil count ≥1.0 × 109/L and off growth factor support for 7 days
  • Total bilirubin ≤1.5× ULN (unless of non-hepatic origin or due to Gilbert's syndrome) or ≤3.0 x ULN if due to GVHD
  • Estimated creatinine clearance ≥30 mL/min

Select Exclusion Criteria

  • Single-organ genitourinary involvement was the only manifestation of cGVHD

ULN=upper limit of normal.

Select Patient Demographics:

  • Median age of patients was 13 years (range: 1-19)
  • Median time since diagnosis was 16.1 months
  • Median number of prior cGVHD treatments was 2 (range: 1-12)
  • Daily corticosteroid dose (prednisone or prednisone equivalent) at baseline was 0.47 mg/kg/day

Study Design Dosing:

  • Patients 12 years of age and older (n=26): 420 mg taken orally once daily until disease progression.
  • Patients 1 to less than 12 years of age (n=21): starting dose of 120 mg/m2, after 14 days of treatment 240 mg/m2 taken orally once daily (up to a dose of 420 mg)

Efficacy in children aged 1 to <22 years with cGVHD who have failed one or more lines of therapy2

Approximately 6 out of 10 patients responded to treatment with IMBRUVICA® based on ORR

The efficacy of IMBRUVICA® was established based on responses evaluated through Week 25 where overall response included complete response or partial response according to the 2014 National Institutes of Health Consensus Development Project Response Criteria.

Overall Response Rate (ORR)*2

*Skin, mouth, liver, upper and lower GI, esophagus, lung, eye, and joint/fascia were the organs/sites considered in evaluating overall response.

CI=confidence interval, CR=complete response, ORR=overall response rate, PR=partial response.

Time to response/duration of response2

Time to first response

Median time to first response was 0.9 month (range: 0.9, 6.1)

The median time from first response to death or new systemic therapies for cGVHD was 14.8 months (95% CI: 4.6, not evaluable).

Median duration of response

*Median duration of response was calculated from first response to progression, death, or new systemic therapy for chronic GVHD.

Improvement in patient-reported symptom bother2

ORR results were supported by exploratory analyses of patient-reported symptom bother, which showed at least a 7-point decrease in Lee Symptom Scale overall summary score through Week 25 in 50% of patients age 12 years and older†

†The Lee Symptom Scale assesses the severity of cGVHD by directly measuring patient symptom burden based on manifestations of the disease (skin, energy, lung, nutritional status, psychological functioning, eye, and mouth)4.

Safety in pediatric patients with cGVHD who have failed one or more lines of therapy2

The iMAGINE trial safety

Median duration of exposure was 7.1 months (range: 0.2, 25.9 months)2

Adverse reactions reported in ≥10% of patients aged 1 to <22 years with cGVHD in iMAGINE2

*Includes multiple ADR terms.

†Includes 1 event with a fatal outcome.

ADR=adverse drug reaction.

Select hematologic laboratory abnormalities (≥10%) that worsened from baseline in patients who received IMBRUVICA® in the iMAGINE trial2

Treatment-emergent Grade 4 neutropenia occurred in 3% of patients.

23% of previously treated pediatric and young adult (aged 1 to <22 years) patients who received IMBRUVICA® in the iMAGINE study discontinued treatment due to adverse reactions2

  • Adverse reactions which resulted in permanent discontinuation in at least 2 patients included hemorrhage
  • Adverse reactions leading to dose reduction occurred in 19% of patients
  • Adverse reactions which required dose reduction in at least two patients included stomatitis.

The safety and effectiveness of IMBRUVICA® in pediatric patients for indications other than cGVHD have not been established.

Please see the downloadable cGVHD brochure for safety, efficacy, dosing, and trial information.

Download

IMBRUVICA® is available as a once-daily oral suspension for children aged 1 to <12 years and as capsules or tablets2

Recommended Dosing in Pediatric Patients Age 1 to <12 years

  • 240 mg/m2 administered orally once daily (up to a maximum daily dose of 420 mg) until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity
  • When a patient no longer requires therapy for the treatment of cGVHD, IMBRUVICA® should be discontinued considering the medical assessment of the individual patient

Recommended Dosing in Pediatric Patients Age ≥12 years

  • 420 mg administered orally once daily until cGVHD progression, recurrence of an underlying malignancy, or unacceptable toxicity
  • IMBRUVICA® can be dosed as a single 420-mg tablet or three 140-mg capsules
  • When a patient no longer requires therapy for the treatment of cGVHD, IMBRUVICA® should be discontinued considering the medical assessment of the individual patient

See full Prescribing Information for complete dosage and administration details.

Recommended dosage based on BSA* for patients 1 to <12 years of age using either IMBRUVICA® capsules/
tablets or oral suspension2

See full Prescribing Information for complete dosage and administration details.

Recommended dosage modifications based on BSA* using either IMBRUVICA® capsules/tablets or oral suspension2

*BSA = body surface area.

Please see full Prescribing Information for volume of IMBRUVICA® needed to reach the recommended dosage.

  • The coadministration of IMBRUVICA® with a strong or moderate CYP3A inhibitor may increase ibrutinib plasma concentrations. Increased ibrutinib concentrations may increase the risk of drug-related toxicity
  • After discontinuation of a CYP3A inhibitor, resume previous dose of IMBRUVICA®
  • Avoid grapefruit and Seville oranges during IMBRUVICA® treatment, as these contain strong or moderate inhibitors of CYP3A

Administer IMBRUVICA® at approximately the same time each day. Swallow tablets or capsules whole with a glass of water. Do not open, break, or chew the capsules. Do not cut, crush, or chew the tablets. Follow Instructions for Use for further administration details of IMBRUVICA® oral suspension. If a dose of IMBRUVICA® is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal dosing schedule the following day. Do not take extra doses of IMBRUVICA® to make up for the missed dose2.

    Dose Modifications for Adverse Reactions in cGVHD

    Dosage modifications for adverse reactions in cGVHD

    If an AR listed below occurs, interrupt IMBRUVICA® therapy at each occurrence of the same AR. Once the AR has improved to Grade 1 or baseline, follow the recommended dosage modifications below2

    Recommended dosage modifications for ARs2

    *Please see Warnings and Precautions section of the Prescribing Information

    †Grading based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria, or International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria for hematologic toxicities in CLL/SLL.

    ‡Evaluate the benefit-risk before resuming treatment.

    §For Grade 4 non-hematologic toxicities, evaluate the benefit-risk before resuming treatment.

    Refer to Dosage and Administration (2.2) Table 3 in the Prescribing Information for recommended dosage modifications based on BSA using either IMBRUVICA® capsules/tablets or oral suspension.

      Patients on CYP3A Inhibitors

      Patients on CYP3A inhibitors may receive IMBRUVICA®2

      In an observational, analytical, retrospective cohort study,

      50% of pediatric patients with allogeneic hematopoietic stem cell transplantation used CYP3A inhibitors in the month before transplantation5

      Dosage modifications for use with CYP3A inhibitors in
      pediatric patients with cGVHD2

      *BSA = body surface area.
      †Modify dose as recommended.
      Refer to Dosage and Administration (2.2) Table 3 in the Prescribing Information for recommended dosage modifications based on BSA using either IMBRUVICA® capsules/tablets or oral suspension.

      Please see full Prescribing Information for volume of IMBRUVICA® needed to reach the recommended dosage.

      • The coadministration of IMBRUVICA® with a strong or moderate CYP3A inhibitor may increase ibrutinib plasma concentrations. Increased ibrutinib concentrations may increase the risk of drug-related toxicity
      • After discontinuation of a CYP3A inhibitor, resume previous dose of IMBRUVICA®
      • Avoid grapefruit and Seville oranges during IMBRUVICA® treatment, as these contain strong or moderate inhibitors of CYP3A

        Patients with hepatic impairment

        Dosage modifications for use in hepatic impairment

        • The recommended dosage is 140 mg daily for patients 12 years of age and older with total bilirubin level >1.5 to 3x upper limit of normal (ULN) (unless of non-hepatic origin or due to Gilbert’s syndrome)
        • The recommended dosage is 80 mg/m2 daily for patients 1 to less than 12 years of age with total bilirubin level >1.5 to 3x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome)
        • Avoid the use of IMBRUVICA® in these patients with total bilirubin level >3x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome)

          Oral Suspension and Administration of Oral suspension

          Administration of IMBRUVICA® oral suspension for patients aged 1 to <12 years2

          The following oral suspension administration overview is not meant to replace the Instructions for Use that are supplied with IMBRUVICA®.

          Please see the full Instructions for Use for details on preparation and administration information.

          Steps for administering IMBRUVICA® to your pediatric patients

          Instruct patients to read the Instructions for Use before administering IMBRUVICA® oral suspension and each time they get a refill.

          Confirm the dosage of IMBRUVICA®

          The recommended dosage of IMBRUVICA® for patients 1 to less than 12 years of age with cGVHD is 240 mg/m2 orally once daily (up to a dose of 420 mg).

          Prepare the dose

          Shake bottle well before each use. Press down and twist cap to remove it. Do not remove the adapter. Utilize the provided syringe to withdraw desired dose, removing any air bubbles prior to administration.

          Administer IMBRUVICA®

          IMBRUVICA® must be administered as soon as possible after being drawn from the bottle. Ensure that the patient drinks water after swallowing the dose of medicine.

          How to store IMBRUVICA® oral suspension

          • Store the bottle upright at temperatures between 36ºF and 77ºF (2ºC and 25ºC)
          • DO NOT freeze.
          • DO NOT use IMBRUVICA® after the expiration date printed on the carton and the bottle after “EXP.”
          • Store IMBRUVICA® and all medications out of sight and reach of children.
          • Discard any unused IMBRUVICA® oral suspension remaining 60 days after first opening the bottle.
          • Ask your pharmacist how to properly dispose of medicine. For syringe disposal, rinse and place in household trash.

          How to store IMBRUVICA® capsules

          • Store bottles at room temperature 20ºC and 25ºC (68ºF to 77ºF).
          • Brief exposure to 15°C to 30°C (59°F to 86°F) permitted (see USP Controlled Room Temperature).
          • Retain in original package until dispensing.

          How to store IMBRUVICA® tablets

          • Store tablets in original packaging 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 (see USP Controlled Room Temperature).

          Please see the downloadable Dosing Brochure for dosing and administration information.

          Download

          Click here to learn more about the IMBRUVICA® By Your Side patient support program

          Click here to see NDC numbers for IMBRUVICA® dosing

          Click here to see IMBRUVICA® Diagnosis Codes

          Support & Resources: Diagnosis Codes

          CR=complete response, DOR=duration of response, NE=not estimable, ORR=overall response rate, PR=partial response.
           

          References: 1. National Comprehensive Cancer Network. Hematopoietic Cell Transplantation (Version 1.2022). 2. IMBRUVICA® (ibrutinib) Prescribing Information. 3. Data on file. 4. Lee S, Cook EF, Soiffer R, et al. Development and validation of a scale to measure symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2002;8(8):444–452. 5. Perez P, Patiño J, Franco AA. Prophylaxis for invasive fungal infection in pediatric patients with allogeneic hematopoietic stem cell transplantation. Blood Res. 2022;57:34-40.

          IMPORTANT SAFETY INFORMATION

          Warnings and Precautions

          Hemorrhage: Fatal bleeding events have occurred in patients who received IMBRUVICA®. Major hemorrhage (≥ Grade 3, serious, or any central nervous system events; e.g., intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) occurred in 4.2% of patients, with fatalities occurring in 0.4% of 2,838 patients who received IMBRUVICA® in 27 clinical trials. Bleeding events of any grade including bruising and petechiae occurred in 39%, and excluding bruising and petechiae occurred in 23% of patients who received IMBRUVICA®, respectively.

          The mechanism for the bleeding events is not well understood.

          Use of either anticoagulant or antiplatelet agents concomitantly with IMBRUVICA® increases the risk of major hemorrhage. Across clinical trials, 3.1% of 2,838 patients who received IMBRUVICA® without antiplatelet or anticoagulant therapy experienced major hemorrhage. The addition of antiplatelet therapy with or without anticoagulant therapy increased this percentage to 4.4%, and the addition of anticoagulant therapy with or without antiplatelet therapy increased this percentage to 6.1%. Consider the risks and benefits of anticoagulant or antiplatelet therapy when co-administered with IMBRUVICA®. Monitor for signs and symptoms of bleeding. 

          Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

          Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 21% of 1,476 patients with B-cell malignancies who received IMBRUVICA® in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA®. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections. 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®. Deaths due to cardiac causes or sudden deaths occurred in 1% of 4,896 patients who received IMBRUVICA® in clinical trials, including in patients who received IMBRUVICA® in unapproved monotherapy or combination regimens. These adverse reactions occurred in patients with and without preexisting hypertension or cardiac comorbidities. Patients with cardiac comorbidities may be at greater risk of these events.

          Grade 3 or greater ventricular tachyarrhythmias were reported in 0.2%, Grade 3 or greater atrial fibrillation and atrial flutter were reported in 3.7%, and Grade 3 or greater cardiac failure was reported in 1.3% of 4,896 patients who received IMBRUVICA® in clinical trials, including in patients who received IMBRUVICA® in unapproved monotherapy or combination regimens. These events have occurred particularly in patients with cardiac risk factors including hypertension and diabetes mellitus, a previous history of cardiac arrhythmias, and in patients with acute infections.

          Evaluate cardiac history and function at baseline, and monitor patients for cardiac arrhythmias and cardiac function. Obtain further evaluation (e.g., ECG, echocardiogram) as indicated for patients who develop symptoms of arrhythmia (e.g., palpitations, lightheadedness, syncope, chest pain), new onset dyspnea, or other cardiovascular concerns. Manage cardiac arrhythmias and cardiac failure appropriately, follow dose modification guidelines, and consider the risks and benefits of continued IMBRUVICA® treatment.

          Hypertension: Hypertension occurred in 19% of 1,476 patients with B-cell malignancies who received IMBRUVICA® in clinical trials. Grade 3 or greater hypertension occurred in 8% of patients. Based on data from a subset of these patients, (N=1,124), the median time to onset was 5.9 months (range, 0 to 24 months). In a long-term safety analysis over 5 years of 1,284 patients with B-cell malignancies treated for a median of 36 months (range, 0 to 98 months), the cumulative rate of hypertension increased over time. The prevalence for Grade 3 or greater hypertension was 4% (year 0-1), 7% (year 1-2), 9% (year 2-3), 9% (year 3-4), and 9% (year 4-5); the overall incidence for the 5-year period was 11%. Monitor blood pressure in patients treated with IMBRUVICA®, initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA® as appropriate, and follow dosage modification guidelines for Grade 3 or higher hypertension.

          Cytopenias: In 645 patients with B-cell malignancies who received IMBRUVICA® as a single agent, grade 3 or 4 neutropenia occurred in 23% of patients, grade 3 or 4 thrombocytopenia in 8% and grade 3 or 4 anemia in 2.8%, based on laboratory measurements. Monitor complete blood counts monthly.

          Second Primary Malignancies: Other malignancies (10%), including non-skin carcinomas (3.9%), occurred among the 1,476 patients with B-cell malignancies who received IMBRUVICA® in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

          Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA®. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

          Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA® and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during the same time period.

          ADVERSE REACTIONS

          B-cell malignancies: The most common adverse reactions (≥30%) in adult patients with B-cell malignancies were thrombocytopenia (55%)*, diarrhea (44%), fatigue (39%), musculoskeletal pain (39%), neutropenia (39%)*, rash (36%), anemia (35%)*, bruising (32%), and nausea (30%).

          The most common Grade ≥ 3 adverse reactions (≥5%) in adult patients with B-cell malignancies were neutropenia (21%)*, thrombocytopenia (14%)*, pneumonia (8%), and hypertension (8%).

          Approximately 9% (CLL/SLL), and 14% (WM) of adult patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL) and 5% (WM) of adult patients discontinued due to adverse reactions.

          cGVHD: The most common adverse reactions (≥20%) in adult or pediatric patients with cGVHD were fatigue (57%), anemia (49%)*, bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, musculoskeletal pain (30%), pyrexia (30%), muscle spasms (29%), stomatitis (29%), hemorrhage (26%), nausea (26%), abdominal pain (23%), pneumonia (23%), and headache (21%).

          The most common Grade 3 or higher adverse reactions (≥5%) reported in adult or pediatric patients with cGVHD were pneumonia (14%), anemia (13%)*, fatigue (12%), pyrexia (11%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), osteonecrosis (9%), stomatitis (9%), hypokalemia (7%), headache (5%), and musculoskeletal pain (5%).

          Discontinuation of IMBRUVICA® treatment due to an adverse reaction occurred in 24% of adult patients and 23% of pediatric patients. Adverse reactions leading to dose reduction occurred in 26% of adult patients and 19% of pediatric patients.

          *Treatment-emergent decreases (all grades) were based on laboratory measurements.

          DRUG INTERACTIONS

          CYP3A Inhibitors: Co-administration of IMBRUVICA® with strong or moderate CYP3A inhibitors may increase ibrutinib plasma concentrations. Increased ibrutinib concentrations may increase the risk of drug-related toxicity. Dose modifications of IMBRUVICA® are recommended when used concomitantly with posaconazole, voriconazole, and moderate CYP3A inhibitors. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA® if strong inhibitors are used short-term (e.g., for ≤ 7 days). Avoid grapefruit and Seville oranges during IMBRUVICA® treatment, as these contain strong or moderate inhibitors of CYP3A. See dose modification guidelines in USPI sections 2.3 and 7.1.

          CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

          SPECIFIC POPULATIONS

          Pediatric Use: The safety and effectiveness of IMBRUVICA® have not been established for the treatment of cGVHD after failure of one or more lines of therapy in pediatric patients less than 1 year of age. The safety and effectiveness of IMBRUVICA® in pediatric patients have not been established in CLL/SLL, CLL/SLL with 17p deletion, WM, or in patients with mature B-cell non-Hodgkin lymphoma.

          In the randomized population from a study that included 35 patients (26 pediatric patients age 5 to less than 17 years) with previously treated mature B-cell non-Hodgkin lymphoma, major hemorrhage and discontinuation of chemoimmunotherapy due to adverse reactions occurred more frequently in the ibrutinib plus chemoimmunotherapy arm compared to the chemoimmunotherapy alone arm.

          Hepatic Impairment:

          Adult Patients with B-cell Malignancies: Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA® in patients with severe hepatic impairment. In patients with mild or moderate impairment, reduce recommended IMBRUVICA® dose and monitor more frequently for adverse reactions of IMBRUVICA®.

          Patients with cGVHD: Avoid use of IMBRUVICA® in patients with total bilirubin level > 3x upper limit of normal (ULN) (unless of non-hepatic origin or due to Gilbert’s syndrome). Reduce recommended dose when administering IMBRUVICA® to patients with total bilirubin level > 1.5 to 3x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).

          Please see full Prescribing Information.

           

          INDICATIONS

          IMBRUVICA® is a kinase inhibitor indicated for the treatment of:

          • Adult patients with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL).
          • Adult patients with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion.
          • Adult patients with Waldenström's macroglobulinemia (WM).
          • Adult and pediatric patients age 1 year and older with chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy.

          IMPORTANT SAFETY INFORMATION

          INDICATIONS

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