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IMBRUVICA (ibrutinib) capsule
[Pharmacyclics, Inc]


Category DEA Schedule Marketing Status
HUMAN PRESCRIPTION DRUG LABEL New Drug Application
Drug Label Sections

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use IMBRUVICA safely and effectively. See full prescribing information for IMBRUVICA.

IMBRUVICA™ (ibrutinib) capsules, for oral use
Initial U.S. Approval: 2013

RECENT MAJOR CHANGES

Indications and Usage (1.2)1/14
Dosage and Administration (2.2, 2.3) 1/14
Warnings and Precautions (5.1, 5.2, 5.3, 5.4, and 5.5)1/14

INDICATIONS AND USAGE

IMBRUVICA is a kinase inhibitor indicated for the treatment of patients with:

  • Mantle cell lymphoma (MCL) who have received at least one prior therapy (1.1).
  • Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy (1.2).

These indications are based on overall response rate. Improvements in survival or disease-related symptoms have not been established (14.1, 14.2).

DOSAGE AND ADMINISTRATION

MCL: 560 mg taken orally once daily (four 140 mg capsules once daily) (2.2).

CLL: 420 mg taken orally once daily (three 140 mg capsules once daily) (2.2).

Capsules should be taken orally with a glass of water. Do not open, break, or chew the capsules (2.1).

DOSAGE FORMS AND STRENGTHS

Capsule: 140 mg (3)

CONTRAINDICATIONS

None 

WARNINGS AND PRECAUTIONS

  • Hemorrhage: Monitor for bleeding (5.1).
  • Infections: Monitor patients for fever and infections and evaluate promptly (5.2).
  • Myelosuppression: Check complete blood counts monthly (5.3).
  • Renal Toxicity: Monitor renal function and maintain hydration (5.4).
  • Second Primary Malignancies: Other malignancies have occurred in patients, including skin cancers, and other carcinomas (5.5).
  • Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the potential risk to a fetus and to avoid pregnancy while taking the drug (5.6).

ADVERSE REACTIONS

The most common adverse reactions (≥20%) in patients with MCL were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (6.1).

The most common adverse reactions (≥20%) in patients with CLL were thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness (6.2).


To report SUSPECTED ADVERSE REACTIONS, contact Pharmacyclics at 1-877-877-3536 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS

CYP3A Inhibitors: Avoid co-administration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce IMBRUVICA dose (2.4, 7.1).

CYP3A Inducers: Avoid co-administration with strong CYP3A inducers (7.2).

USE IN SPECIFIC POPULATIONS

Hepatic Impairment: Avoid use of IMBRUVICA in patients with baseline hepatic impairment (8.7).

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 2/2014

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Mantle Cell Lymphoma

IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established [see Clinical Studies (14.1)].

1.2 Chronic Lymphocytic Leukemia

IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established [see Clinical Studies (14.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Guidelines

Administer IMBRUVICA orally once daily at approximately the same time each day. Swallow the capsules whole with water. Do not open, break, or chew the capsules.

2.2 Dosage

Mantle Cell Lymphoma

The recommended dose of IMBRUVICA for MCL is 560 mg (four 140 mg capsules) orally once daily.

Chronic Lymphocytic Leukemia

The recommended dose of IMBRUVICA for CLL is 420 mg (three 140 mg capsules) orally once daily.

2.3 Dose Modifications for Adverse Reactions

Interrupt IMBRUVICA therapy for any Grade 3 or greater non-hematological, Grade 3 or greater neutropenia with infection or fever, or Grade 4 hematological toxicities. Once the symptoms of the toxicity have resolved to Grade 1 or baseline (recovery), IMBRUVICA therapy may be reinitiated at the starting dose. If the toxicity reoccurs, reduce dose by one capsule (140 mg per day). A second reduction of dose by 140 mg may be considered as needed. If these toxicities persist or recur following two dose reductions, discontinue IMBRUVICA.

Recommended dose modifications for these toxicities are described below:

Toxicity OccurrenceMCL Dose Modification After Recovery
Starting Dose = 560 mg
CLL Dose Modification After Recovery Starting Dose = 420 mg
FirstRestart at 560 mg dailyRestart at 420 mg daily
SecondRestart at 420 mg dailyRestart at 280 mg daily
ThirdRestart at 280 mg dailyRestart at 140 mg daily
FourthDiscontinue IMBRUVICADiscontinue IMBRUVICA

2.4 Dose Modifications for Use with CYP3A Inhibitors

Avoid co-administration with strong or moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition.

Concomitant use of strong CYP3A inhibitors which would be taken chronically (e.g., ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone) is not recommended. For short-term use (treatment for 7 days or less) of strong CYP3A inhibitors (e.g., antifungals and antibiotics) consider interrupting IMBRUVICA therapy until the CYP3A inhibitor is no longer needed [see Drug Interactions (7.1)].

Reduce IMBRUVICA dose to 140 mg if a moderate CYP3A inhibitor must be used (e.g., fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, grapefruit products and ciprofloxacin) [see Drug Interactions (7.1)].

Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs of IMBRUVICA toxicity.

2.5 Missed Dose

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. Extra capsules of IMBRUVICA should not be taken to make up for the missed dose.

3 DOSAGE FORMS AND STRENGTHS

140 mg capsules

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Hemorrhage

Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily.

The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies.

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 have occurred with IMBRUVICA therapy. At least 25% of patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions (6.1) and (6.2)]. Monitor patients for fever and infections and evaluate promptly.

5.3 Myelosuppression

Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL.

Monitor complete blood counts monthly.

5.4 Renal Toxicity

Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels. Maintain hydration.

5.5 Second Primary Malignancies

Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA. Four percent of patients with MCL, had skin cancers and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas.

5.6 Embryo-Fetal Toxicity

Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling:

Because clinical trials are conducted under widely variable conditions, adverse event 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.

6.1 Mantle Cell Lymphoma

The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months.

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (See Tables 1 and 2).

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.

Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1.

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Mantle Cell Lymphoma (N=111)
System Organ ClassPreferred TermAll Grades (%)Grade 3 or 4 (%)
Gastrointestinal disordersDiarrhea515
Nausea310
Constipation250
Abdominal pain245
Vomiting230
Stomatitis171
Dyspepsia110
Infections and infestationsUpper respiratory tract infection340
Urinary tract infection143
Pneumonia147
Skin infections145
Sinusitis131
General disorders and administrative site conditionsFatigue415
Peripheral edema353
Pyrexia181
Asthenia143
Skin and subcutaneous tissue disordersBruising300
Rash253
Petechiae110
Musculoskeletal and connective tissue disordersMusculoskeletal pain371
Muscle spasms140
Arthralgia110
Respiratory, thoracic and mediastinal disordersDyspnea274
Cough190
Epistaxis110
Metabolism and nutrition disordersDecreased appetite212
Dehydration124
Nervous system disordersDizziness140
Headache130
Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111)
Percent of Patients (N=111)
All Grades (%)Grade 3 or 4 (%)
*
Based on laboratory measurements and adverse reactions
Platelets Decreased5717
Neutrophils Decreased4729
Hemoglobin Decreased419

Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients.

Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression.

Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.

6.2 Chronic Lymphocytic Leukemia

The data described below reflect exposure to IMBRUVICA in a clinical trial that included 48 patients with previously treated CLL treated with 420 mg daily with a median treatment duration of 15.6 months.

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness (See Tables 3 and 4).

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain.

Adverse reactions from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Table 3.

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Chronic Lymphocytic Leukemia (N=48)
System Organ ClassPreferred TermAll Grades (%)Grade 3 or 4 (%)
*
One patient death due to histiocytic sarcoma.
Gastrointestinal disordersDiarrhea634
Constipation232
Nausea212
Stomatitis210
Vomiting192
Abdominal pain150
Dyspepsia130
Infections and infestationsUpper respiratory tract infection482
Sinusitis216
Skin infection176
Pneumonia108
Urinary tract infection100
General disorders and administrative site conditionsFatigue314
Pyrexia252
Peripheral edema230
Asthenia134
Chills130
Skin and subcutaneous tissue disordersBruising542
Rash270
Petechiae170
Respiratory, thoracic and mediastinal disordersCough190
Oropharyngeal pain150
Dyspnea100
Musculoskeletal and connective tissue disordersMusculoskeletal pain276
Arthralgia230
Muscle spasms192
Nervous system disordersDizziness210
Headache192
Peripheral neuropathy100
Metabolism and nutrition disordersDecreased appetite172
Neoplasms benign, malignant, unspecifiedSecond malignancies*10*0
Injury, poisoning and procedural complicationsLaceration102
Psychiatric disordersAnxiety100
Insomnia100
Vascular disordersHypertension178
Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48)
Percent of Patients (N=48)
All Grades (%)Grade 3 or 4 (%)
*
Based on laboratory measurements per IWCLL criteria and adverse reactions
Platelets Decreased7110
Neutrophils Decreased5427
Hemoglobin Decreased440

Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% of patients.

Thirty-eight percent of patients had shifts from normal to elevated uric acid levels on study including 4% with values above 10 mg/dL.

7 DRUG INTERACTIONS

Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A.

7.1 CYP3A Inhibitors

In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng ∙ hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg).

Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4)].

Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3)].

7.2 CYP3A Inducers

Administration of IMBRUVICA with strong inducers of CYP3A decrease ibrutinib plasma concentrations by approximately 10-fold.

Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John's Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.6)].

Risk Summary

Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus.

Animal Data

Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral 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 post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily.

8.3 Nursing Mothers

It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of IMBRUVICA in pediatric patients has not been established.

8.5 Geriatric Use

Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients.

Of the 48 patients treated for CLL, 52% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. A greater number of adverse events were reported in those 65 years of age and older. Grade 3 or higher adverse events occurred more frequently among elderly patients (80% of patients 65 and older versus 61% of younger patients).

8.6 Renal Impairment

Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 × upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3)].

8.8 Females and Males of Reproductive Potential

Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations (8.1)].

11 DESCRIPTION

Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK). It is a white to off-white solid with the empirical formula C25H24N6O2 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:

Chemical Structure

IMBRUVICA (ibrutinib) capsules for oral administration are supplied as white opaque capsules that contain 140 mg ibrutinib as the active ingredient. Each capsule also contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The capsule shell contains gelatin, titanium dioxide and black ink. Each white opaque capsule is marked with "ibr 140 mg" in black ink.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK's role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.

12.2 Pharmacodynamics

In patients with recurrent B-cell lymphoma > 90% occupancy of the BTK active site in peripheral blood mononuclear cells was observed up to 24 hours after ibrutinib doses of ≥ 2.5 mg/kg/day (≥ 175 mg/day for average weight of 70 kg).

12.3 Pharmacokinetics

Absorption

Ibrutinib is absorbed after oral administration with a median Tmax of 1 to 2 hours. Ibrutinib exposure increases with doses up to 840 mg. The steady-state AUC (mean ± standard deviation) observed in patients at 560 mg is 953 ± 705 ng∙h/mL and in patients at 420 mg is 680 ± 517 ng∙h/mL. Administration with food increases ibrutinib exposure approximately 2-fold compared with administration after overnight fasting.

Distribution

Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 to 1000 ng/mL. The apparent volume of distribution at steady state (Vd,ss/F) is approximately 10000 L.

Metabolism

Metabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites primarily by cytochrome P450, CYP3A, and to a minor extent by CYP2D6. The active metabolite, PCI-45227, is a dihydrodiol metabolite with inhibitory activity towards BTK approximately 15 times lower than that of ibrutinib. The range of the mean metabolite to parent ratio for PCI-45227 at steady-state is 1 to 2.8.

Elimination

Apparent clearance (CL/F) is approximately 1000 L/h. The half-life of ibrutinib is 4 to 6 hours.

Ibrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After a single oral administration of radiolabeled [14C]-ibrutinib in healthy subjects, approximately 90% of radioactivity was excreted within 168 hours, with the majority (80%) excreted in the feces and less than 10% accounted for in urine. Unchanged ibrutinib accounted for approximately 1% of the radiolabeled excretion product in feces and none in urine, with the remainder of the dose being metabolites.

Age

Age (37 to 84 years) does not alter ibrutinib systemic clearance.

Gender

Gender does not alter ibrutinib systemic clearance.

Renal Impairment

Ibrutinib is not significantly cleared renally; urinary excretion of metabolites is < 10% of the dose. Creatinine clearance > 25 mL/min had no influence on the exposure to IMBRUVICA. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or in patients on dialysis.

Hepatic Impairment

Ibrutinib is metabolized in the liver. No clinical trials have been completed in subjects with impaired hepatic function. Preliminary PK data from an ongoing trial in subjects with hepatic impairment indicate that ibrutinib exposure is approximately 6-fold higher in subjects (N=3) with moderate hepatic impairment (Child-Pugh B) compared with mean exposures observed in healthy volunteer trials.

Drug Interactions

Coadministration of Ibrutinib with CYP3A Inhibitors

In a sequential design trial of 18 healthy volunteers, a single dose of 120 mg of IMBRUVICA was administered alone on Day 1 and a single dose of 40 mg of IMBRUVICA was administered on Day 7 in combination with 400 mg of ketoconazole (given daily on Days 4 – 9). Ketoconazole increased ibrutinib dose-normalized Cmax and AUC 29-fold and 24-fold, respectively. Simulations using physiologically-based pharmacokinetic (PBPK) models suggested that moderate CYP3A inhibitors (diltiazem and erythromycin) may increase the AUC of ibrutinib 6 to 9-fold in fasted condition.

Coadministration of Ibrutinib with CYP3A Inducers

Preliminary PK data from an ongoing dedicated drug interaction trial and simulations using PBPK indicate that rifampin (a strong CYP3A inducer) can decrease ibrutinib Cmax and AUC by more than 10-fold. Simulations using PBPK suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC of ibrutinib up to 3-fold.

Coadministration of Ibrutinib with CYP Substrates

In vitro studies indicated that ibrutinib (I/Ki < 0.07 using mean Cmax at 560 mg) and PCI-45227 (I/Ki < 0.03) are unlikely to be inhibitors of any major CYPs at clinical doses. Both ibrutinib and the PCI-45227 are weak inducers of CYP450 isoenzymes in vitro.

Coadministration of Ibrutinib with Substrates of Transporters

In vitro studies indicated that ibrutinib is not a substrate of p-glycoprotein (P-gp). Systemic ibrutinib is unlikely to be an inhibitor of P-gp at clinical doses ([I]1/Ki < 0.1). However, it may have an effect on P-gp substrates in the GI tract due to higher local concentrations after an oral dose. Co-administration of oral narrow therapeutic index P-gp substrates (e.g., digoxin) with IMBRUVICA may increase their blood concentration.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with ibrutinib.

Ibrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a chromosome aberration assay in mammalian (CHO) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in mice at doses up to 2000 mg/kg.

Fertility studies with ibrutinib have not been conducted in animals. In the general toxicology studies conducted in rats and dogs, orally administered ibrutinib did not result in adverse effects on reproductive organs.

14 CLINICAL STUDIES

14.1 Mantle Cell Lymphoma

The safety and efficacy of IMBRUVICA in patients with MCL who have received at least one prior therapy were evaluated in an open-label, multi-center, single-arm trial of 111 previously treated patients. The median age was 68 years (range, 40 to 84 years), 77% were male, and 92% were Caucasian. At baseline, 89% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 42 months, and median number of prior treatments was 3 (range, 1 to 5 treatments), including 11% with prior stem cell transplant. At baseline, 39% of subjects had at least one tumor ≥ 5 cm, 49% had bone marrow involvement, and 54% had extranodal involvement at screening.

IMBRUVICA was administered orally at 560 mg once daily until disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group (IWG) for non-Hodgkin's lymphoma (NHL) criteria. The primary endpoint in this study was investigator-assessed overall response rate (ORR). Responses to IMBRUVICA are shown in Table 5.

Table 5: Overall Response Rate (ORR) and Duration of Response (DOR) Based on Investigator Assessment in Patients with Mantle Cell Lymphoma
Total (N=111)
CI = confidence interval; CR = complete response; PR = partial response; NR = not reached
ORR (%)65.8
  95% CI (%)(56.2, 74.5)
  CR (%)17.1
  PR (%)48.6
Median DOR months (95% CI)17.5 (15.8, NR)

An Independent Review Committee (IRC) performed independent reading and interpretation of imaging scans. The IRC review demonstrated an ORR of 69%.

The median time to response was 1.9 months.

Lymphocytosis

Upon initiation of IMBRUVICA, a temporary increase in lymphocyte counts (i.e., ≥ 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 33% of patients in the MCL study. The onset of isolated lymphocytosis occurs during the first few weeks of IMBRUVICA therapy and resolves by a median of 8 weeks.

14.2 Chronic Lymphocytic Leukemia

The safety and efficacy of IMBRUVICA in patients with CLL who have received at least one prior therapy were evaluated in an open-label, multi-center trial of 48 previously treated patients. The median age was 67 years (range, 37 to 82 years), 71% were male, and 94% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 80 months and the median number of prior treatments was 4 (range, 1 to 12 treatments). At baseline, 46% of subjects had at least one tumor ≥ 5 cm.

IMBRUVICA was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The ORR and DOR were assessed using a modified version of the International Workshop on CLL Criteria by an Independent Review Committee. The ORR was 58.3% (95% CI: 43.2%, 72.4%), all partial responses. None of the patients achieved a complete response. The DOR ranged from 5.6 to 24.2+ months. The median DOR was not reached.

Lymphocytosis

Upon initiation of IMBRUVICA, an increase in lymphocyte counts (i.e., ≥ 50% increase from baseline and above absolute lymphocyte count of 5,000/mcL) occurred in 77% of patients in the CLL study. The onset of isolated lymphocytosis occurs during the first month of IMBRUVICA therapy and resolves by a median of 23 weeks (range 1 – 104+ weeks).

16 HOW SUPPLIED/STORAGE AND HANDLING

The white opaque 140 mg capsules marked with "ibr 140 mg" in black ink are available 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). Excursions are permitted between 15°C and 30°C (59°F to 86°F). Retain in original package.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information)

  • Hemorrhage:
    Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions (5.1)].
  • Infections:
    Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions (5.2)].
  • Renal toxicity:
    Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration [see Warnings and Precautions (5.4)].
  • Second primary malignancies:
    Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions (5.5)].
  • Embryo-fetal toxicity:
    Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions (5.6)].
  • Inform patients to take IMBRUVICA orally once daily according to their physician's instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1)].
  • Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5)].
  • Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions (6)]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.
  • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].
  • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists.

Active ingredient made in China.

Distributed and Marketed by:
Pharmacyclics, Inc.
Sunnyvale, CA USA 94085
and
Marketed by:
Janssen Biotech, Inc.
Horsham, PA USA 19044

Patent http://www.imbruvica.com
IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc.

©Pharmacyclics, Inc. 2014
Issued: February 2014

This Patient Information has been approved by the U.S. Food and Drug Administration.
Revised: 02/2014
Patient Information
IMBRUVICA (im-BRU-vih-kuh)

(ibrutinib) capsules
What is IMBRUVICA?
IMBRUVICA is a prescription medicine used to treat people with:
  • Mantle cell lymphoma (MCL) who have received at least one prior treatment
  • Chronic lymphocytic leukemia (CLL) who have received at least one prior treatment
It is not known if IMBRUVICA is safe and effective in children.
What should I tell my healthcare provider before taking IMBRUVICA?
Before you take IMBRUVICA, tell your healthcare provider about all of your medical conditions, including if you:
  • have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA for any planned medical, surgical, or dental procedure.
  • have bleeding problems
  • have liver problems
  • are pregnant or plan to become pregnant. IMBRUVICA can harm your unborn baby. You should not become pregnant while taking IMBRUVICA.
  • are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will take IMBRUVICA or breastfeed. You should not do both.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking IMBRUVICA with certain other medicines may affect how IMBRUVICA works and can cause side effects.
How should I take IMBRUVICA?
  • Take IMBRUVICA exactly as your healthcare provider tells you to take it.
  • Take IMBRUVICA 1 time a day.
  • Swallow IMBRUVICA capsules whole with a glass of water. Do not open, break, or chew IMBRUVICA capsules.
  • Take IMBRUVICA at about the same time each day.
  • If you miss a dose of IMBRUVICA take it as soon as you remember on the same day. Take your next dose of IMBRUVICA at your regular time on the next day. Do not take 2 doses of IMBRUVICA on the same day to make up for a missed dose.
What should I avoid while taking IMBRUVICA?
  • You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) while you are taking IMBRUVICA. These products may increase the amount of IMBRUVICA in your blood.
What are the possible side effects of IMBRUVICA?
IMBRUVICA may cause serious side effects, including:
  • Bleeding problems can happen during treatment with IMBRUVICA that can be serious. Tell your healthcare provider if you have any signs of bleeding, including: blood in your stools or black stools (looks like tar), pink or brown urine, unexpected bleeding or bleeding that is severe or that you can not control, vomit blood or vomit looks like coffee grounds, cough up blood or blood clots, increased bruising, feel dizzy or weak, confusion, change in your speech, or a headache that lasts a long time. Your risk of bleeding may increase if you are also taking a blood thinner medicine.
  • Infections can happen during treatment with IMBRUVICA. Infections can be serious and may lead to death. Tell your healthcare provider if you have fever, chills, or any other signs or symptoms of an infection while taking IMBRUVICA.
  • Decrease in blood cell counts. Your healthcare provider should do monthly blood tests to check your blood counts.
  • Kidney problems. Kidney failure and death have happened with IMBRUVICA treatment. Drink fluids during treatment with IMBRUVICA to help prevent too much fluid loss (dehydration). Your healthcare provider should do blood tests to check how well your kidneys are working.
  • Second primary cancers. New cancers have happened in people who have been treated with IMBRUVICA, including cancers of the skin or other organs.
The most common side effects of IMBRUVICA in people with mantle cell lymphoma (MCL) include: low blood platelet count, diarrhea, low white blood cell count, low red blood cell count, fatigue, muscle and bone pain, swelling of legs and feet, upper respiratory tract infection, nausea, bruising, shortness of breath, constipation, rash, stomach (abdomen) pain, vomiting, and decreased appetite.
The most common side effects of IMBRUVICA in people with chronic lymphocytic leukemia (CLL) include: low blood platelet count, diarrhea, bruising, low white blood cell count, low red blood cell count, upper respiratory tract infection, fatigue, muscle and bone pain, rash, fever, constipation, swelling of legs and feet, joint pain, nausea, mouth sores, sinus infection, and dizziness.
Diarrhea is a common side effect in people who take IMBRUVICA. Tell your healthcare provider if you have diarrhea that does not go away.
These are not all the possible side effects of IMBRUVICA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store IMBRUVICA?
  • Store IMBRUVICA at room temperature between 68°F to 77°F (20°C to 25°C).
  • Keep IMBRUVICA in the original container with the lid tightly closed.
Keep IMBRUVICA and all medicines out of the reach of children.
General information about the safe and effective use of IMBRUVICA
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use IMBRUVICA for a condition for which it was not prescribed. Do not give IMBRUVICA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about IMBRUVICA that is written for health professionals.
What are the ingredients in IMBRUVICA?
Active ingredient: ibrutinib
Inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The capsule shell contains gelatin, titanium dioxide and black ink.
Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and
Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 For more information call 1-877-877-3536

PRINCIPAL DISPLAY PANEL - 90 Capsule Bottle Carton

NDC 57962-140-09

Imbruvica™
(ibrutinib) capsules

140 mg

Each capsule contains: ibrutinib 140 mg
Swallow capsules whole with water

90 Capsules

Rx Only

pharmacyclics®

Janssen

PRINCIPAL DISPLAY PANEL - 90 Capsule Bottle Carton
IMBRUVICA 
ibrutinib capsule
Product Information
Product TypeHUMAN PRESCRIPTION DRUG LABELItem Code (Source)NDC:57962-140
Route of AdministrationORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
Ibrutinib (Ibrutinib) Ibrutinib140 mg
Inactive Ingredients
Ingredient NameStrength
sodium lauryl sulfate 
croscarmellose sodium 
cellulose, microcrystalline 
Magnesium stearate 
Product Characteristics
ColorWHITEScoreno score
ShapeCAPSULESize22mm
FlavorImprint Code ibr140mg
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:57962-140-0990 in 1 BOTTLE, PLASTIC
2NDC:57962-140-12120 in 1 BOTTLE, PLASTIC
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA20555211/07/2013
Labeler - Pharmacyclics, Inc (791179526)
Establishment
NameAddressID/FEIBusiness Operations
Pharmacyclics, Inc791179526ANALYSIS(57962-140)

Revised: 2/2014
 
Pharmacyclics, Inc

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