DULLARMA

Ibrutinib is a small molecule that acts as an irreversible potent inhibitor of Burton's tyrosine kinase.

It is designated as a targeted covalent drug and presented as a promising activity in B-cell malignancies in clinical trials.

Ibrutinib was developed by Pharmacyclics

Inc and was first approved by the FDA in November for the treatment of mantle cell lymphoma (MCL) under accelerated approval; 16 however, in April 2023, the drug manufacturer withdrew the accelerated approvals for ibrutinib in the US.

Ibrutinib was approved by the EMA in October 2014 19 and by Health Canada in November 2014.

It is currently approved for the treatment of various conditions, such as chronic lymphocytic leukemia (CLL), Waldenström's Macroglobulinemia, and chronic graft versus host disease (cGVHD) in August 2017.

Notably, ibrutinib became the first FDA-approved cGVHD treatment for children in August 2017.

Ibrutinib is indicated for the treatment of the following conditions.

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) In the US, it is used in adult patients with or without 17p deletion. 17, 19 In Europe and Canada, it is used as a single agent or combined with rituximab, obinutuzumab, or venetoclax in previously untreated CLL patients.

In patients who have received at least one prior therapy, it is used as a single agent or in combination with bendamustine and rituximab. 19, 20 Waldenström's macroglobulinemia It is used alone 17, 19, 20 or with rituximab. 19, 20 In Europe, it is approved for patients who have received at least one prior therapy or in first-line treatment for patients unsuitable for chemoimmunotherapy.

Chronic graft-versus-host disease (cGVHD) In the US, it is approved in patients aged one year and older after the prior failure of one or more lines of systemic therapy.

In Canada, it is approved in adults with steroid-dependent or refractory cGVHD.

Mantle cell lymphoma (MCL) In Europe and Canada, ibrutinib is also indicated to treat relapsed or refractory MCL in adults. 19, 20 Marginal zone lymphoma (MZL) In Canada, it is approved for adults who require systemic therapy and have received at least one prior anti-CD20-based therapy.

In vitro studies have shown an induction of CLL cell apoptosis even in presence of prosurvival factors.

It has also been reported an inhibition of CLL cell survival and proliferation as well as an impaired in cell migration and a reduction in the secretion of chemokines such as CCL3 and CCL4.

The latter effect has been shown to produce regression in xenograft mouse models.

Clinical studies for relapsed/refractory CLL in phase I and II showed an approximate 71% of overall response rate. 7, 8.

In the case of relapsed/refractory mantle cell lymphoma, approximately 70% of the tested patients presented a partial or complete response. 7, 9.

In clinical trials for relapsed/refractory diffuse large B-cell lymphoma, a partial response was found in between 15-20% of the patients studied; while for patients with relapsed/refractory Waldenstrom's macroglobulinemia, a partial response was observed in over 75% of the patients tested.

Finally, for patients with relapsed/refractory follicular lymphoma, a partial to complete response was obtained in approximately 54% of the patients.

Ibrutinib is rapidly absorbed after oral administration and it presents a Cmax, tmax and AUC of approximately 35 ng/ml, 1-2 hour and 953 mg.h/ml respectively.

The volume of distribution at steady-state of ibrutinib is in approximately 10,000 L.

Three metabolic pathways have been identified according to the possible metabolites.

These pathways are the hydroxylation of the phenyl group (M35), the opening of the piperidine with a reduction of the primary alcohol (M34) and the oxidation to a carboxylic acid and epoxidation of the ethylene followed by a hydrolysis to the formation of dihydrodiol (PCI-45227).

The latter metabolite presents also 15 times lower inhibitory activity against BTK.

The metabolism of ibrutinib is mainly performed by CYP3A5 and CYP3A4. and in a minor extent it is seen to be performed by CYP2D6.

Hover over products below to view reaction partners Ibrutinib PCI-7503 (M23) PCI-48303 (M26) PCI-45227 (M37) PCI-45773 (M35) M17 PCI-45741 (M25) M20 PCI-45752 (M34) M17 M24.

The cumulative excretion of ibrutinib in urine is of about 7.8% of the administered dose and most of this excretion is found during the first 24 hours after administration.

In feces, the cumulative excretion accounts for 80% of the administered dose and the excretion occurs within 48 hours of the initial administration.

The total excretion of ibrutinib during the first 168 hours after initial administration accounts for 88.5% of the administered dose.

The elimination half-life of ibrutinib is of approximately 4-6 hours.

In patients with normal renal function, the clearance rate is in the range of 112-159 ml/min.

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Ibrutinib was not showed to present a mutagenic potential in bacterial assays, nor clastogenic in chromosome aberration assays in mammalian cells or in bone marrow micronucleus assays in mice.

Carcinogenicity or effects on fertility have not been determined.

and WM: 420 mg taken orally once daily. cGVHD: ◦ Patients 12 years and older: 420 mg taken orally once daily. ◦ Patients to less than 12 years of age: 240 mg/m 2 taken orally once daily (up to a dose of 420 mg) .

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. 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.

CLL/SLL, IMBRUVICA can be administered as a single agent, in combination with rituximab or obinutuzumab, or in combination with bendamustine and rituximab (BR).

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 to less than 12 years of age with cGVHD is 240 mg/m 2 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.

Table 1: Recommended dosage based on body surface area (BSA) for patients to less than 12 years of age using either IMBRUVICA capsules/tablets or oral suspension Recommended dose to achieve 240 mg/m 2 BSA* (m 2 ) 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.

IMBRUVICA at approximately the same time each day. Swallow tablets or capsules whole with a glass of water.

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.

Table 2: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction a,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/m 2 Grade 2 cardiac failure First Restart at 280 mg daily c Restart at 160 mg/m 2 daily c Second Restart at 140 mg daily c Restart at 80 mg/m 2 daily c Third Discontinue IMBRUVICA Discontinue IMBRUVICA Grade 3 cardiac arrhythmias First Restart at 280 mg daily c Restart at 160 mg/m 2 daily c 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 toxicities d Grade 3 or 4 neutropenia with infection or fever Grade 4 hematological toxicities First Restart at 280 mg daily Restart at 160 mg/m 2 daily c Second Restart at 140 mg daily Restart at 80 mg/m 2 daily c Third Discontinue IMBRUVICA Discontinue IMBRUVICA a. 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.

Table 3: Recommended dosage modifications based on BSA using either IMBRUVICA capsules/tablets or oral suspension Recommended dose to achieve 160 mg/m 2 Recommended dose to achieve 80 mg/m 2 BSA* (m 2 ) 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.

• 0.4 mL > 0.4 to 0.5.

• 0.5 mL > 0.5 to 0.6.

• 0.6 mL > 0.6 to 0.7.

• 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: Table 4: Recommended Dosage Modifications for Use with CYP3A Inhibitors Patient Population Coadministered Drug Recommended IMBRUVICA Dosage B-cell Malignancies Moderate CYP3A inhibitor 280 mg once daily Modify dose as recommended.

Voriconazole 200 mg twice daily Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily 140 mg once daily Modify dose as recommended.

Posaconazole suspension 200 mg three times daily or 400 mg twice daily Posaconazole intravenously 300 mg once daily Posaconazole delayed-release tablets 300 mg once daily 70 mg once daily Interrupt dose as recommended.

Other strong

CYP3A inhibitors 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 Moderate CYP3A inhibitor 420 mg once daily Modify dose as recommended.

Voriconazole 200 mg twice daily Posaconazole suspension 100 mg once daily, 100 mg twice daily, or 200 mg twice daily 280 mg once daily Modify dose as recommended.

Posaconazole suspension 200 mg three times daily or 400 mg twice daily Posaconazole intravenously 300 mg once daily Posaconazole delayed-release tablets 300 mg once daily 140 mg once daily Interrupt dose as recommended.

Patients 1 year to less than 12 years of age with cGVHD Moderate CYP3A inhibitors 240 mg/m 2 once daily Modify dose as recommended.

Voriconazole for suspension 9 mg/kg (maximum dose: 350 mg) twice daily 160 mg/m 2 once daily Posaconazole at any dosage 80 mg/m 2 once daily Other strong CYP3A inhibitors Avoid concomitant use.

After discontinuation of a

CYP3A inhibitor, resume previous dose of IMBRUVICA. 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) .

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/m 2 daily for patients 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).

IMBRUVICA in these patients with total bilirubin level > 3 x ULN (unless of non-hepatic origin or due to Gilbert’s syndrome) .

The 70 mg capsules are supplied as yellow opaque capsules, marked with “ibr 70 mg” in black ink, in white HDPE bottles with a child-resistant closure: 28 capsules per bottle: NDC 57962-070-28 The 140 mg capsules are supplied as white opaque capsules, marked with “ibr 140 mg” in black ink, in white HDPE bottles with a child-resistant closure: 90 capsules per bottle: NDC 57962-140-09 120 capsules per bottle: NDC 57962-140-12 Store bottles 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.

Retain in original package until dispensing.

IMBRUVICA (ibrutinib) tablets are supplied in 3 strengths in the following packaging configurations: 140 mg tablets: Yellow green to green round tablets debossed with “ibr” on one side and “140” on the other side.

Carton of one folded blister card containing two 14-count blister strips for a total of 28 tablets: NDC 57962-014-28 280 mg tablets: Purple oblong tablets debossed with “ibr” on one side and “280” on the other side.

Carton of one folded blister card containing two 14-count blister strips for a total of 28 tablets: NDC 57962-280-28 420 mg tablets: Yellow green to green oblong tablets debossed with “ibr” on one side and “420” on the other side.

Carton of one folded blister card containing two 14-count blister strips for a total of 28 tablets: NDC 57962-420-28 Store tablets in original packaging at room temperature 20°C to 25°C (68°F to 77°F).

IMBRUVICA (ibrutinib) oral suspension is a white to off-white suspension supplied as 108 mL in a 150 mL amber glass bottle with a pre-inserted bottle adapter and a child-resistant closure.

Each mL contains 70 mg of ibrutinib.

The oral suspension bottle is provided in a carton with two 3 mL reusable oral dosing syringes: NDC 57962-007-12.

Store the oral suspension bottle at 2°C to 25°C (36°F to 77°F).

Do not freeze.

Dispense in original sealed container.

Do not use if the carton seal is broken or missing.

Discard any unused

IMBRUVICA oral suspension remaining 60 days after first opening the bottle.

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.

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.

Ibrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 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.

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 in adults.

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) .

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 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.

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.

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.