Ibrutinib

FDA Drug Information • Also known as: Imbruvica

Brand Names: Imbruvica
Dosage Form: POWDER
Product Type: BULK INGREDIENT

Description

11 DESCRIPTION Ibrutinib is a kinase inhibitor. It is a white to off-white solid with the empirical formula C 25 H 24 N 6 O 2 and a molecular weight 440.50. Ibrutinib is freely soluble in dimethyl sulfoxide, soluble in methanol and practically insoluble in water. The chemical name for ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and has the following structure: IMBRUVICA (ibrutinib) is available as immediate-release oral capsules, immediate-release oral tablets, and immediate-release oral suspension. IMBRUVICA (ibrutinib) capsules for oral use are available in the following dosage strengths: 70 mg and 140 mg. Each capsule contains ibrutinib (active ingredient) and the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The capsule shell contains gelatin, titanium dioxide, yellow iron oxide (70 mg capsule only), and black ink. IMBRUVICA (ibrutinib) tablets for oral use are available in the following dosage strengths: 140 mg, 280 mg, and 420 mg. Each tablet contains ibrutinib (active ingredient) and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. The film coating for each tablet contains ferrosoferric oxide (140 mg, 280 mg, and 420 mg tablets), polyvinyl alcohol, polyethylene glycol, red iron oxide (280 mg tablets), talc, titanium dioxide, and yellow iron oxide (140 mg and 420 mg tablets). IMBRUVICA (ibrutinib) oral suspension contains 70 mg/mL ibrutinib (active ingredient) and the following inactive ingredients: benzyl alcohol, citric acid monohydrate, disodium hydrogen phosphate, hypromellose, microcrystalline cellulose and carboxymethylcellulose sodium, purified water and sucralose. The following structure for Ibrutinib is kinase inhibitor. It is a white to off-white solid with...

What Is Ibrutinib Used For?

1 INDICATIONS AND USAGE IMBRUVICA is a kinase inhibitor indicated for the treatment of: Adult patients with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) ( 1.1 ). Adult patients with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion ( 1.2 ). Adult patients with Waldenström’s macroglobulinemia (WM) ( 1.3 ). 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 ( 1.4 ). 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.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION CLL/SLL and WM : 420 mg taken orally once daily ( 2.1 ). cGVHD : ◦ Patients 12 years and older: 420 mg taken orally once daily ( 2.1 ). ◦ Patients 1 to less than 12 years of age: 240 mg/m 2 taken orally once daily (up to a dose of 420 mg) ( 2.1 ). 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 ). 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/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 1 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. 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...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hemorrhage [see Warnings and Precautions ( 5.1 )] Infections [see Warnings and Precautions ( 5.2 )] Cardiac Arrhythmias, Cardiac Failure, and Sudden Death [see Warnings and Precautions ( 5.3 )] Hypertension [see Warnings and Precautions ( 5.4 )] Cytopenias [see Warnings and Precautions ( 5.5 )] Second Primary Malignancies [see Warnings and Precautions ( 5.6 )] Hepatotoxicity, including DILI [see Warning s and Precautions ( 5.7 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.8 )] The most common (≥30%) adverse reactions in patients with B-cell malignancies are thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea ( 6 ). The most common (≥20%) adverse reactions in adult or pediatric patients with cGVHD are fatigue, anemia, bruising, diarrhea, thrombocytopenia, musculoskeletal pain, pyrexia, muscle spasms, stomatitis, hemorrhage, nausea, abdominal pain, pneumonia, and headache ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact AbbVie at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Unless otherwise specified, the pooled safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to IMBRUVICA in 6 trials. IMBRUVICA was administered as a single agent at 420 mg orally once daily (475 patients), as a single agent at 560 mg orally once daily [1.3 times the recommended adult dosage (174 patients)], and in combination with other drugs at 420 mg orally once daily (827 patients) in patients with B-cell malignancies. In this pooled safety population of 1,476 patients, 87% were exposed for 6 months or longer and 68% were exposed for greater than one year. The most common adverse reactions (≥ 30%) were thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, bruising, and nausea. Certain subsections in the WARNINGS AND PRECAUTIONS include patients who received IMBRUVICA in unapproved monotherapy or combination regimens. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma The data described below reflect exposure to IMBRUVICA in one single-arm, open-label clinical trial (Study 1102) and five randomized controlled clinical trials (RESONATE, RESONATE-2, HELIOS, iLLUMINATE, and E1912) in patients with CLL/SLL (n=2,016 total, including n=1,133 patients exposed to IMBRUVICA). In general, patients with creatinine clearance (CLcr) ≤ 30 mL/min, AST or ALT ≥ 2.5 x ULN, or total bilirubin ≥ 1.5 x ULN (unless of non-hepatic origin) were excluded from these trials. In Study E1912, patients with AST or ALT > 3 x ULN or total bilirubin > 2.5 x ULN were excluded. Study 1102 included 51 patients with previously treated CLL/SLL. RESONATE included 386 randomized patients with previously treated CLL or SLL who received single agent IMBRUVICA or ofatumumab. RESONATE-2 included 267 randomized patients with treatment naïve CLL or SLL who were 65 years or older and received single agent IMBRUVICA or chlorambucil. HELIOS included 574 randomized patients with previously treated CLL or SLL who received IMBRUVICA in combination with BR or placebo in combination with BR. iLLUMINATE included 228 randomized patients with treatment naïve CLL/SLL who were 65 years or older or with coexisting medical conditions and received IMBRUVICA in combination with obinutuzumab or chlorambucil in combination with obinutuzumab. E1912 included 510 patients with previously untreated CLL/SLL who were 70 years or younger and received IMBRUVICA in combination with rituximab or received fludarabine, cyclophosphamide, and rituximab (FCR). The most common adverse...

Drug Interactions

7 DRUG INTERACTIONS CYP3A Inhibitors: Modify IMBRUVICA dose as described ( 2.3 , 7.1 ). CYP3A Inducers: Avoid coadministration with strong CYP3A inducers ( 7.2 ). 7.1 Effect of CYP3A Inhibitors on Ibrutinib The coadministration of IMBRUVICA with a strong or moderate CYP3A inhibitor may increase ibrutinib plasma concentrations [see Clinical Pharmacology ( 12.3 )] . 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 [see Dosage and Administration ( 2.3 )]. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if these inhibitors will be used short-term (such as anti-infectives for seven days or less) [see Dosage and Administration ( 2.3 ) ] . Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain strong or moderate inhibitors of CYP3A. 7.2 Effect of CYP3A Inducers on Ibrutinib The coadministration of IMBRUVICA with strong CYP3A inducers may decrease ibrutinib concentrations. Avoid coadministration with strong CYP3A inducers [see Clinical Pharmacology ( 12.3 ) ] .

Contraindications

4 CONTRAINDICATIONS None None ( 4 )

Pregnancy and Breastfeeding

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...

Overdosage

10 OVERDOSAGE There is no specific experience in the management of ibrutinib overdose in patients. One healthy subject experienced reversible Grade 4 hepatic enzyme increases (AST and ALT) after a dose of 1680 mg. Closely monitor patients who ingest more than the recommended dosage and provide appropriate supportive treatment.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Capsules 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 (see USP Controlled Room Temperature). Retain in original package until dispensing. Tablets The 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). Brief exposure to 15°C to 30°C (59°F to 86°F) permitted (see USP Controlled Room Temperature). Oral Suspension The 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...

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.