Imbruvica
(ibrutinib)Dosage & Administration
Tablets or capsules should be taken orally with a glass of water. Do not open, break, or chew the capsules. Do not cut, crush, or chew the tablets. See full prescribing information for oral suspension administration instructions .
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Imbruvica Prescribing Information
1.1 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
1.2 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with 17p deletion
IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with 17p deletion.
1.3 Waldenström’s Macroglobulinemia
IMBRUVICA is indicated for the treatment of adult patients with Waldenström’s macroglobulinemia (WM).
1.4 Chronic Graft versus Host Disease
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.
2.1 Recommended Dosage
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenström’s Macroglobulinemia
The recommended dosage of IMBRUVICA for CLL/SLL and WM is 420 mg orally once daily until disease progression or unacceptable toxicity.
For CLL/SLL, IMBRUVICA can be administered as a single agent, in combination with rituximab or obinutuzumab, or in combination with bendamustine and rituximab (BR).
For WM, IMBRUVICA can be administered as a single agent or in combination with rituximab.
When administering IMBRUVICA in combination with rituximab or obinutuzumab, consider administering IMBRUVICA prior to rituximab or obinutuzumab when given on the same day.
Chronic Graft versus Host Disease
The recommended dosage of IMBRUVICA for patients age 12 years and older with cGVHD is 420 mg orally once daily, and 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), 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 dose to achieve 240 mg/m2 | ||
| BSA* (m2) Range | Dose (mg) of IMBRUVICA Capsules/Tablets to Administer | Volume (mL) of IMBRUVICA Oral Suspension (70 mg/mL) to Administer |
| > 0.3 to 0.4 | - | 1.2 mL |
| > 0.4 to 0.5 | - | 1.5 mL |
| > 0.5 to 0.6 | - | 1.9 mL |
| > 0.6 to 0.7 | - | 2.2 mL |
| > 0.7 to 0.8 | 210 mg | 2.6 mL |
| > 0.8 to 0.9 | 210 mg | 2.9 mL |
| > 0.9 to 1 | 210 mg | 3.3 mL |
| > 1 to 1.1 | 280 mg | 3.6 mL |
| > 1.1 to 1.2 | 280 mg | 4 mL |
| > 1.2 to 1.3 | 280 mg | 4.3 mL |
| > 1.3 to 1.4 | 350 mg | 4.6 mL |
| > 1.4 to 1.5 | 350 mg | 5 mL |
| > 1.5 to 1.6 | 350 mg | 5.3 mL |
| > 1.6 | 420 mg | 6 mL |
*BSA = body surface area.
Administration
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 schedule the following day. Do not take extra doses of IMBRUVICA to make up for the missed dose.
2.2 Dosage Modifications for Adverse Reactions
For adverse reactions listed in Table 2, interrupt IMBRUVICA therapy. Once the adverse reaction has improved to Grade 1 or baseline (recovery), follow the recommended dosage modifications (see Table 2).
| Adverse Reactiona,b | Occurrence | Dose Modification for CLL/SLL, WM, and Patients 12 Years or older with cGVHD After Recovery Starting Dose = 420 mg | Dose Modification for Patients 1 Year to less than 12 Years with cGVHD After Recovery Starting Dose = 240 mg/m2 |
| Grade 2 cardiac failure | First | Restart at 280 mg dailyc | Restart at 160 mg/m2 dailyc |
| Second | Restart at 140 mg dailyc | Restart at 80 mg/m2 dailyc | |
| Third | Discontinue IMBRUVICA | Discontinue IMBRUVICA | |
| Grade 3 cardiac arrhythmias | First | Restart at 280 mg dailyc | Restart at 160 mg/m2 dailyc |
| Second | Discontinue IMBRUVICA | Discontinue IMBRUVICA | |
| Grade 3 or 4 cardiac failure Grade 4 cardiac arrhythmias | First | Discontinue IMBRUVICA | Discontinue IMBRUVICA |
| Other Grade 3 or 4 non-hematological toxicitiesd Grade 3 or 4 neutropenia with infection or fever Grade 4 hematological toxicities | First | Restart at 280 mg daily | Restart at 160 mg/m2 dailyc |
| Second | Restart at 140 mg daily | Restart at 80 mg/m2 dailyc | |
| Third | Discontinue IMBRUVICA | Discontinue IMBRUVICA |
a [see Warnings and Precautions ( 5)].
b 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.
c Evaluate the benefit-risk before resuming treatment.
d For Grade 4 non-hematologic toxicities, evaluate the benefit-risk before resuming treatment.
| Recommended dose to achieve 160 mg/m2 | Recommended dose to achieve 80 mg/m2 | |||
| BSA* (m2) Range | Dose (mg) of IMBRUVICA Capsules/Tablets to Administer | Volume (mL) of IMBRUVICA Oral Suspension (70 mg/mL) to Administer | Dose (mg) of IMBRUVICA Capsules/Tablets to Administer | Volume (mL) of IMBRUVICA Oral Suspension (70 mg/mL) to Administer |
| > 0.3 to 0.4 | - | 0.8 mL | - | 0.4 mL |
| > 0.4 to 0.5 | - | 1 mL | - | 0.5 mL |
| > 0.5 to 0.6 | - | 1.3 mL | - | 0.6 mL |
| > 0.6 to 0.7 | - | 1.5 mL | - | 0.7 mL |
| > 0.7 to 0.8 | 140 mg | 1.7 mL | 70 mg | 0.9 mL |
| > 0.8 to 0.9 | 140 mg | 1.9 mL | 70 mg | 1 mL |
| > 0.9 to 1 | 140 mg | 2.2 mL | 70 mg | 1.1 mL |
| > 1 to 1.1 | 140 mg | 2.4 mL | 70 mg | 1.2 mL |
| > 1.1 to 1.2 | 210 mg | 2.6 mL | - | 1.3 mL |
| > 1.2 to 1.3 | 210 mg | 2.9 mL | - | 1.4 mL |
| > 1.3 to 1.4 | 210 mg | 3.1 mL | - | 1.5 mL |
| > 1.4 to 1.5 | 210 mg | 3.3 mL | 140 mg | 1.7 mL |
| > 1.5 to 1.6 | 280 mg | 3.5 mL | 140 mg | 1.8 mL |
| > 1.6 | 280 mg | 4 mL | 140 mg | 2 mL |
*BSA = body surface area.
2.3 Dosage Modifications for Use with CYP3A Inhibitors
Recommended dosage modifications are described below [see Drug Interactions ( 7.1)]:
| Patient Population | Coadministered Drug | Recommended IMBRUVICA Dosage |
| B-cell Malignancies |
| 280 mg once daily Modify dose as recommended [see Dosage and Administration ( 2.2)]. |
| 140 mg once daily Modify dose as recommended [see Dosage and Administration ( 2.2)]. | |
| 70 mg once daily Interrupt dose as recommended [see Dosage and Administration ( 2.2)]. | |
| Avoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt IMBRUVICA. | |
| Patients 12 years and older with cGVHD |
| 420 mg once daily Modify dose as recommended [see Dosage and Administration ( 2.2)]. |
| 280 mg once daily Modify dose as recommended [see Dosage and Administration ( 2.2)]. | |
| 140 mg once daily Interrupt dose as recommended [see Dosage and Administration ( 2.2)]. | |
| Avoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt IMBRUVICA. | |
| Patients 1 year to less than 12 years of age with cGVHD |
| 240 mg/m2 once daily Modify dose as recommended [see Dosage and Administration ( 2.2)]. |
| 160 mg/m2 once daily | |
| 80 mg/m2 once daily | |
| Avoid concomitant use. If these inhibitors will be used short-term (such as anti-infectives for seven days or less), interrupt IMBRUVICA. |
After discontinuation of a CYP3A inhibitor, resume previous dose of IMBRUVICA [see Dosage and Administration ( 2.1), Drug Interactions ( 7.1)].
2.4 Dosage Modifications for Use in Hepatic Impairment
Adult Patients with B-cell Malignancies
The recommended dosage is 140 mg daily for patients with mild hepatic impairment (Child-Pugh class A).
The recommended dosage is 70 mg daily for patients with moderate hepatic impairment (Child-Pugh class B).
Avoid the use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations ( 8.6), Clinical Pharmacology ( 12.3)].
Patients with cGVHD
The recommended dosage is 140 mg daily for patients 12 years of age and older with total bilirubin level >1.5 to 3 x 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 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome).
Avoid the use of IMBRUVICA in these patients with total bilirubin level > 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome) [see Use in Specific Populations ( 8.6), Clinical Pharmacology ( 12.3)].
Capsules:
Each 70 mg capsule is a yellow, opaque capsule marked with “ibr 70 mg” in black ink.
Each 140 mg capsule is a white, opaque capsule marked with “ibr 140 mg” in black ink.
Tablets:
Each 140 mg tablet is a yellow green to green round tablet debossed with “ibr” on one side and “140” on the other side.
Each 280 mg tablet is a purple oblong tablet debossed with “ibr” on one side and “280” on the other side.
Each 420 mg tablet is a yellow green to green oblong tablet debossed with “ibr” on one side and “420” on the other side.
Oral Suspension:
70 mg/mL, white to off-white suspension.
8.1 Pregnancy
Risk Summary
IMBRUVICA can cause fetal harm based on findings from animal studies. There are no available data on IMBRUVICA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis at exposures up to 3-20 times the clinical dose of 420 mg daily produced embryofetal toxicity including structural abnormalities (see Data). Advise pregnant women of the potential risk to a fetus.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Data
Animal Data
Ibrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased resorptions and post-implantation loss. The dose of 80 mg/kg/day in rats is approximately 20 times the exposure in patients with CLL/SLL or WM administered a dose of 420 mg daily. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in rats is approximately 8 times the exposure (AUC) in patients administered a dose of 420 mg daily.
Ibrutinib was also administered orally to pregnant rabbits during the period of organogenesis at doses of 5, 15, and 45 mg/kg/day. Ibrutinib at a dose of 15 mg/kg/day or greater was associated with skeletal variations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated with increased resorptions and post-implantation loss. The dose of 15 mg/kg/day in rabbits is approximately 2.8 times the exposure in patients with CLL/SLL or WM administered a dose of 420 mg daily.
8.2 Lactation
Risk Summary
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. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with IMBRUVICA and for 1 week after the last dose.
8.3 Females and Males of Reproductive Potential
IMBRUVICA can cause fetal harm when administered to pregnant women [see Use in Specific Populations ( 8.1)].
Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating IMBRUVICA.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with IMBRUVICA and for 1 month after the last dose.
Males
Advise males with female partners of reproductive potential to use effective contraception during treatment with IMBRUVICA and for 1 month following the last dose.
8.4 Pediatric Use
Chronic GVHD
The safety and effectiveness of IMBRUVICA have been established for treatment of cGVHD after failure of one or more lines of systemic therapy in pediatric patients 1 year of age and older.
Use of IMBRUVICA for this indication is supported by evidence from iMAGINE, a study which included pediatric patients age 1 year and older with previously treated cGVHD, including patients in the following age groups: one patient 1 year to less than 2 years of age, 20 patients 2 years to less than 12 years of age, and 19 patients 12 years to less than 17 years of age. Additional supportive efficacy data was provided from Study 1129 in adults [see Adverse Reactions ( 6.1), Clinical Pharmacology ( 12.3), and Clinical Studies ( 14.3)].
The recommended dosage of IMBRUVICA in patients age 12 years and older is the same as that in adults, and the recommended dosage in patients age 1 year to less than 12 years old is based on body-surface area (BSA) [see Dosage and Administration ( 2.1)].
The safety and effectiveness of IMBRUVICA have not been established for this indication in pediatric patients less than 1 year of age.
Mature B-cell Non-Hodgkin Lymphoma
The safety and effectiveness of IMBRUVICA in combination with chemoimmunotherapy were assessed but have not been established based on an open-label, randomized study (NCT02703272) in 35 patients, which included 26 pediatric patients age 5 to less than 17 years, with previously treated mature B-cell non-Hodgkin lymphoma. The study was stopped for futility. In the randomized population, 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.
CLL/SLL, CLL/SLL with 17p deletion, WM
The safety and effectiveness of IMBRUVICA in pediatric patients have not been established in CLL/SLL, CLL/SLL with 17p deletion, or WM.
8.5 Geriatric Use
Of 992 patients in clinical studies of IMBRUVICA for B-cell malignancies or cGVHD, 62% were ≥ 65 years of age, while 22% were ≥ 75 years of age [see Clinical Studies ( 14.1, 14.2, 14.3)]. No overall differences in effectiveness were observed between younger and older patients. Anemia (all grades), pneumonia (Grade 3 or higher), thrombocytopenia, hypertension, and atrial fibrillation occurred more frequently among older patients treated with IMBRUVICA [see Adverse Reactions ( 6.1)].
8.6 Hepatic Impairment
Adult Patients with B-cell Malignancies
Avoid use of IMBRUVICA in patients with severe hepatic impairment (Child-Pugh class C). The safety of IMBRUVICA has not been evaluated in patients with mild to severe hepatic impairment by Child-Pugh criteria.
Reduce the recommended dose when administering IMBRUVICA to patients with mild or moderate hepatic impairment (Child-Pugh class A and B). Monitor patients more frequently for adverse reactions of IMBRUVICA [see Dosage and Administration ( 2.4), Clinical Pharmacology ( 12.3)].
Patients with cGVHD
Avoid use of IMBRUVICA in patients with total bilirubin level > 3 x 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 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome) [see Dosage and Administration ( 2.4)].
8.7 Plasmapheresis
Management of hyperviscosity in WM patients may include plasmapheresis before and during treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required.
None
5.1 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 [see Adverse Reactions ( 6.1)].
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 [see Clinical Studies ( 14)].
5.2 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 [see Adverse Reactions ( 6.1, 6.2)]. 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.
5.3 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 [see Adverse Reactions ( 6.1)].
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 [see Dosage and Administration ( 2.2)], and consider the risks and benefits of continued IMBRUVICA treatment.
5.4 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 [see Adverse Reactions ( 6.1)]. 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 [see Dosage and Administration ( 2.2)].
5.5 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 [see Adverse Reactions ( 6.1)].
Monitor complete blood counts monthly.
5.6 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 [see Adverse Reactions ( 6.1)]. The most frequent second primary malignancy was non-melanoma skin cancer (6%).
5.7 Hepatotoxicity, Including Drug-Induced Liver Injury
Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including IMBRUVICA.
Evaluate bilirubin and transaminases at baseline and throughout treatment with IMBRUVICA. For patients who develop abnormal liver tests after IMBRUVICA, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold IMBRUVICA. Upon confirmation of DILI, discontinue IMBRUVICA.
5.8 Tumor Lysis Syndrome
Tumor lysis syndrome has been infrequently reported with IMBRUVICA [see Adverse Reactions ( 6.2)]. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.
5.9 Embryo-Fetal Toxicity
Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis caused embryo-fetal toxicity including malformations at exposures that were 3-20 times higher than those reported in patients with hematologic malignancies. 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. [see Use in Specific Populations ( 8.1)].