等待内容更新

依鲁替尼胶囊说明书

【适应证和用途】

 

  Imbruvica是一种激酶抑制剂适用为以下患者的治疗：

 

  ⑴ 淋巴瘤（MCL）曾接受至少一种既往治疗。

 

  根据总反应率授权加速批准为这个适应证。继续批准这个适应证可能取决于在验证性试验中证实临床获益。

 

  ⑵ 慢性淋巴细胞白血病（CLL）曾接受至少一种既往治疗。

 

  ⑶ 慢性淋巴细胞白血病有17p缺失。

 

  【剂量和给药方法】

 

  MCL: 560 mg口服每天1次（4粒140 mg胶囊每天1次）。

 

  CLL和WM: 420 mg口服每天1次（3粒140 mg胶囊每天1次）。

 

  应用一杯水口服胶囊。不要打开，破裂，或咀嚼胶囊。

 

  【剂型和规格】

 

  胶囊：140mg

 

  【警告和注意事项】

 

  （1）出血：对出血监视。

 

  （2）感染：监视对发热和感染患者和及时评价。

 

  （3）骨髓抑制：每月检查全血细胞计数。

 

  （4）肾毒性：监视肾功能和保持水化。

 

  （5）第二个原发恶性肿瘤：患者中曾发生其他恶性肿瘤，包括皮肤癌，和其他癌。

 

  （6）胚胎-胎儿毒性：可致胎儿危害。忠告妇女对胎儿潜在风险当妊娠时避免服药。

 

  【不良反应】

 

  在有B-细胞恶性病患者（MCL，CLL，WM） 最常见不良反应（≥25%）是血小板减少，中性粒细胞减少，腹泻，贫血，疲乏，肌肉骨骼痛，瘀伤，恶心，上呼吸道感染，和皮疹。

 

  【药物相互作用】

 

  CYP3A抑制剂：避免与强和中度CYP3A抑制剂共同给药。如必须使用中度CYP3A抑制剂，减低 Imbruvica剂量。

 

  CYP3A诱导剂：避免与强CYP3A诱导剂共同给药。

 

  【特殊人群中使用】

 

  肝受损：有中度或严重基线肝受损患者避免使用Imbruvica。有轻度受损患者减低Imbruvica剂量。 

 

Imbruvica

Dosage Form: capsule

Medically reviewed on Sep 1, 2018

 

 

 

 

 

Indications and Usage for ImbruvicaMantle Cell Lymphoma

Imbruvica is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial [see Clinical Studies (14.1)].

 

 

 

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Imbruvica is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

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.

 

 

 

 

Waldenström's Macroglobulinemia

Imbruvica is indicated for the treatment of adult patients with Waldenström's macroglobulinemia (WM).

Marginal Zone Lymphoma

Imbruvica is indicated for the treatment of adult patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy.

Accelerated approval was granted for this indication based on overall response rate [see Clinical Studies (14.4)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Chronic Graft versus Host Disease

Imbruvica is indicated for the treatment of adult patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy.

Imbruvica Dosage and AdministrationDosing Guidelines

Administer Imbruvica orally once daily at approximately the same time each day. The dose 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.

Recommended Dosage

Mantle Cell Lymphoma and Marginal Zone Lymphoma

The recommended dose of Imbruvica for MCL and MZL is 560 mg orally once daily until disease progression or unacceptable toxicity.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma and Waldenström's Macroglobulinemia

The recommended dose of Imbruvica for CLL/SLL and WM as a single agent, in combination with rituximab for WM, or in combination with bendamustine and rituximab for CLL/SLL is 420 mg orally once daily until disease progression or unacceptable toxicity.

When administering Imbruvica in combination with rituximab, consider administering Imbruvica prior to rituximab when given on the same day.

Chronic Graft versus Host Disease

The recommended dose of Imbruvica for cGVHD is 420 mg orally once daily 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.

Dose Modifications for Adverse Reactions

Interrupt Imbruvica therapy for any Grade 3 or greater non-hematological toxicities, 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 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 are described below:

Toxicity Occurrence	Dose Modification for MCL and MZL After Recovery Starting Dose = 560 mg	Dose Modification for CLL/SLL, WM, and cGVHD After Recovery Starting Dose = 420 mg
First	Restart at 560 mg daily	Restart at 420 mg daily
Second	Restart at 420 mg daily	Restart at 280 mg daily
Third	Restart at 280 mg daily	Restart at 140 mg daily
Fourth	Discontinue Imbruvica	Discontinue Imbruvica

Dose Modifications for Use with CYP3A Inhibitors

Recommended dose modifications are described below [see Drug Interactions (7.1)]:

Patient Population	Coadministered Drug	Recommended Imbruvica Dose
B-Cell Malignancies	· Moderate CYP3A inhibitor	280 mg once daily Modify dose as recommended [see Dosage and Administration (2.3)].
	· 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 [see Dosage and Administration (2.3)].
	· Posaconazole suspension 200 mg three times daily or 400 mg twice daily · Posaconazole IV injection 300 mg once daily · Posaconazole delayed-release tablets 300 mg once daily	70 mg once daily Interrupt dose as recommended [see Dosage and Administration (2.3)].
	· 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.
Chronic Graft versus Host Disease	· Moderate CYP3A inhibitor	420 mg once daily Modify dose as recommended [see Dosage and Administration (2.3)].
	· 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 [see Dosage and Administration (2.3)].
	· Posaconazole suspension 200 mg three times daily or 400 mg twice daily · Posaconazole IV injection 300 mg once daily · Posaconazole delayed-release tablets 300 mg once daily	140 mg once daily Interrupt dose as recommended [see Dosage and Administration (2.3)].
	· 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.

After discontinuation of a CYP3A inhibitor, resume previous dose of Imbruvica [see Dosage and Administration (2.2) and Drug Interactions (7.1)].

Dose Modifications for Use in Hepatic Impairment

The recommended dose is 140 mg daily for patients with mild hepatic impairment (Child-Pugh class A).

The recommended dose 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) and Clinical Pharmacology (12.3)].

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 doses of Imbruvica should not be taken to make up for the missed dose.

Dosage Forms and Strengths

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.

Each 560 mg tablet is a yellow to orange oblong tablet debossed with "ibr" on one side and "560" on the other side.

Contraindications

None

Warnings and PrecautionsHemorrhage

Fatal bleeding events have occurred in patients treated with Imbruvica. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 3% of patients, with fatalities occurring in 0.3% of 1,011 patients exposed to Imbruvica in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% of patients treated with Imbruvica.

The mechanism for the bleeding events is not well understood.

Imbruvica may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs 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)].

Infections

Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with Imbruvica therapy. Grade 3 or greater infections occurred in 24% of 1,011 patients exposed to 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.

Cytopenias

Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent Imbruvica.

Monitor complete blood counts monthly.

Cardiac Arrhythmias

Fatal and serious cardiac arrhythmias have occurred with Imbruvica therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,011 patients exposed to Imbruvica in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias. See Additional Important Adverse Reactions (6.1).

Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of Imbruvica treatment and follow dose modification guidelines [see Dosage and Administration (2.3)].

Hypertension

Hypertension has occurred in 12% of 1,011 patients treated with Imbruvica in clinical trials with a median time to onset of 5 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting Imbruvica. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate.

Second Primary Malignancies

Other malignancies (9%) including non-skin carcinomas (2%) have occurred in 1,011 patients treated with Imbruvica in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).

Tumor Lysis Syndrome

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

Embryo-Fetal Toxicity

Based on findings in animals, Imbruvica can cause fetal harm when administered to a pregnant woman. Administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis caused embryo-fetal toxicity including malformations at exposures that were 2-20 times higher than those reported in patients with hematologic malignancies. Advise women to avoid becoming pregnant while taking Imbruvica and for 1 month after cessation of therapy. 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)].

Adverse Reactions

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

· Hemorrhage [see Warnings and Precautions (5.1)]

· Infections [see Warnings and Precautions (5.2)]

· Cytopenias [see Warnings and Precautions (5.3)]

· Cardiac Arrhythmias [see Warnings and Precautions (5.4)]

· Hypertension [see Warnings and Precautions (5.5)]

· Second Primary Malignancies [see Warnings and Precautions (5.6)]

· Tumor Lysis Syndrome [see Warnings and Precautions (5.7)]

Clinical Trials Experience

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.

Mantle Cell Lymphoma

The data described below reflect exposure to Imbruvica in a clinical trial (Study 1104) 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.

Fatal and serious cases of renal failure have occurred with Imbruvica therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients.

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 MCL (N=111)
Body System	Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
Gastrointestinal disorders	Diarrhea	51	5
	Nausea	31	0
	Constipation	25	0
	Abdominal pain	24	5
	Vomiting	23	0
	Stomatitis	17	1
	Dyspepsia	11	0
Infections and infestations	Upper respiratory tract infection	34	0
	Urinary tract infection	14	3
	Pneumonia	14	7
	Skin infections	14	5
	Sinusitis	13	1
General disorders and administration site conditions	Fatigue	41	5
	Peripheral edema	35	3
	Pyrexia	18	1
	Asthenia	14	3
Skin and subcutaneous tissue disorders	Bruising	30	0
	Rash	25	3
	Petechiae	11	0
Musculoskeletal and connective tissue disorders	Musculoskeletal pain	37	1
	Muscle spasms	14	0
	Arthralgia	11	0
Respiratory, thoracic and mediastinal disorders	Dyspnea	27	4
	Cough	19	0
	Epistaxis	11	0
Metabolism and nutrition disorders	Decreased appetite	21	2
	Dehydration	12	4
Nervous system disorders	Dizziness	14	0
	Headache	13	0
Table 2: Treatment-Emergent* Hematologic Laboratory Abnormalities 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 Decreased	57	17
Neutrophils Decreased	47	29
Hemoglobin Decreased	41	9

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.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

The data described below reflect exposure in one single-arm, open-label clinical trial (Study 1102) and three randomized controlled clinical trials (RESONATE, RESONATE-2, and HELIOS) in patients with CLL/SLL (n=1278 total and n=668 patients exposed to Imbruvica). Study 1102 included 51 patients with previously treated CLL/SLL, RESONATE included 391 randomized patients with previously treated CLL or SLL who received single agent Imbruvica or ofatumumab, RESONATE-2 included 269 randomized patients 65 years or older with treatment naïve-CLL or SLL who received single agent Imbruvica or chlorambucil, and HELIOS included 578 randomized patients with previously treated CLL or SLL who received Imbruvica in combination with bendamustine and rituximab or placebo in combination with bendamustine and rituximab.

The most commonly occurring adverse reactions in Studies 1102, RESONATE, RESONATE-2, and HELIOS in patients with CLL/SLL receiving Imbruvica (≥ 20%) were neutropenia, thrombocytopenia, anemia, diarrhea, musculoskeletal pain, nausea, rash, bruising, fatigue, pyrexia and hemorrhage. Four to 10 percent of patients receiving Imbruvica in Studies 1102, RESONATE, RESONATE-2, and HELIOS discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each). Adverse reactions leading to dose reduction occurred in approximately 6% of patients.

Study 1102

Adverse reactions and laboratory abnormalities from the CLL/SLL trial (N=51) using single agent Imbruvica 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of ≥ 10% with a median duration of treatment of 15.6 months are presented in Tables 3 and 4.

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL/SLL (N=51) in Study 1102
Body System	Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
* One patient death due to histiocytic sarcoma.
Gastrointestinal disorders	Diarrhea	59	4
	Constipation	22	2
	Nausea	20	2
	Stomatitis	20	0
	Vomiting	18	2
	Abdominal pain	14	0
	Dyspepsia	12	0
Infections and infestations	Upper respiratory tract infection	47	2
	Sinusitis	22	6
	Skin infection	16	6
	Pneumonia	12	10
	Urinary tract infection	12	2
General disorders and administration site conditions	Fatigue	33	6
	Pyrexia	24	2
	Peripheral edema	22	0
	Asthenia	14	6
	Chills	12	0
Skin and subcutaneous tissue disorders	Bruising	51	2
	Rash	25	0
	Petechiae	16	0
Respiratory, thoracic and mediastinal disorders	Cough	22	0
	Oropharyngeal pain	14	0
	Dyspnea	12	0
Musculoskeletal and connective tissue disorders	Musculoskeletal pain	25	6
	Arthralgia	24	0
	Muscle spasms	18	2
Nervous system disorders	Dizziness	20	0
	Headache	18	2
Metabolism and nutrition disorders	Decreased appetite	16	2
Neoplasms benign, malignant, unspecified	Second malignancies*	12*	0
Vascular disorders	Hypertension	16	8
Table 4: Treatment-Emergent* Hematologic Laboratory Abnormalities in Patients with CLL/SLL (N=51) in Study 1102
	Percent of Patients (N=51)
	All Grades (%)	Grade 3 or 4 (%)
* Based on laboratory measurements per IWCLL criteria and adverse reactions.
Platelets Decreased	69	12
Neutrophils Decreased	53	26
Hemoglobin Decreased	43	0

RESONATE

Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to Imbruvica with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in RESONATE in patients with previously treated CLL/SLL.

Table 5: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the Imbruvica Treated Arm in Patients with CLL/SLL in RESONATE
Body System Adverse Reaction	Imbruvica (N=195)			Ofatumumab (N=191)
	All Grades (%)	Grade 3 or 4 (%)		All Grades (%)		Grade 3 or 4 (%)
Subjects with multiple events for a given ADR term are counted once only for each ADR term. The body system and individual ADR terms are sorted in descending frequency order in the Imbruvica arm.
* Includes multiple ADR terms
Gastrointestinal disorders
Diarrhea	48	4		18		2
Nausea	26	2		18		0
Stomatitis*	17	1		6		1
Constipation	15	0		9		0
Vomiting	14	0		6		1
General disorders and administration site conditions
Pyrexia	24	2		15		1
Infections and infestations
Upper respiratory tract infection	16	1		11		2
Pneumonia*	15	10		13		9
Sinusitis*	11	1		6		0
Urinary tract infection	10	4		5		1
Skin and subcutaneous tissue disorders
Rash*	24	3		13		0
Petechiae	14	0		1		0
Bruising*	12	0		1		0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	28	2		18		1
Arthralgia	17	1		7		0
Nervous system disorders
Headache	14	1		6		0
Dizziness	11	0		5		0
Injury, poisoning and procedural complications
Contusion	11	0		3		0
Eye disorders
Vision blurred	10	0		3		0
Table 6: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with CLL/SLL in RESONATE
	Imbruvica (N=195)		Ofatumumab (N=191)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)		Grade 3 or 4 (%)
Neutrophils Decreased	51	23	57		26
Platelets Decreased	52	5	45		10
Hemoglobin Decreased	36	0	21		0

RESONATE-2

Adverse reactions described below in Table 7 reflect exposure to Imbruvica with a median duration of 17.4 months. The median exposure to chlorambucil was 7.1 months in RESONATE-2.

Table 7: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the Imbruvica Treated Arm in Patients with CLL/SLL in RESONATE-2
Body System Adverse Reaction	Imbruvica (N=135)		Chlorambucil (N=132)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Subjects with multiple events for a given ADR term are counted once only for each ADR term. The body system and individual ADR terms are sorted in descending frequency order in the Imbruvica arm.
* Includes multiple ADR terms
Gastrointestinal disorders
Diarrhea	42	4	17	0
Stomatitis*	14	1	4	1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	36	4	20	0
Arthralgia	16	1	7	1
Muscle spasms	11	0	5	0
Eye disorders
Dry eye	17	0	5	0
Lacrimation increased	13	0	6	0
Vision blurred	13	0	8	0
Visual acuity reduced	11	0	2	0
Skin and subcutaneous tissue disorders
Rash*	21	4	12	2
Bruising*	19	0	7	0
Infections and infestations
Skin infection*	15	2	3	1
Pneumonia*	14	8	7	4
Urinary tract infections	10	1	8	1
Respiratory, thoracic and mediastinal disorders
Cough	22	0	15	0
General disorders and administration site conditions
Peripheral edema	19	1	9	0
Pyrexia	17	0	14	2
Vascular disorders
Hypertension*	14	4	1	0
Nervous system disorders
Headache	12	1	10	2

HELIOS

Adverse reactions described below in Table 8 reflect exposure to Imbruvica + BR with a median duration of 14.7 months and exposure to placebo + BR with a median of 12.8 months in HELIOS in patients with previously treated CLL/SLL.

Table 8: Adverse Reactions Reported in at Least 10% of Patients and at Least 2% Greater in the Imbruvica Arm in Patients with CLL/SLL in HELIOS
Body System Adverse Reaction	Ibrutinib + BR (N=287)		Placebo + BR (N=287)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
The body system and individual ADR terms are sorted in descending frequency order in the Imbruvica arm. <1 used for frequency above 0 and below 0.5%
* Includes multiple ADR terms
Blood and lymphatic system disorders
Neutropenia*	66	61	60	55
Thrombocytopenia*	34	16	26	16
Skin and subcutaneous tissue disorders
Rash *	32	4	25	1
Bruising *	20	<1	8	<1
Gastrointestinal disorders
Diarrhea	36	2	23	1
Abdominal pain	12	1	8	<1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	29	2	20	0
Muscle spasms	12	<1	5	0
General disorders and administration site conditions
Pyrexia	25	4	22	2
Vascular disorders
Hemorrhage*	19	2	9	1
Hypertension *	11	5	5	2
Infections and infestations
Bronchitis	13	2	10	3
Skin infection*	10	3	6	2
Metabolism and nutrition disorders
Hyperuricemia	10	2	6	0

Atrial fibrillation of any grade occurred in 7% of patients treated with Imbruvica + BR and 2% of patients treated with placebo + BR. The frequency of Grade 3 and 4 atrial fibrillation was 3% in patients treated with Imbruvica + BR and 1% in patients treated with placebo + BR.

Waldenström's Macroglobulinemia and Marginal Zone Lymphoma

The data described below reflect exposure to Imbruvica in three single-arm open-label clinical trials (Study 1118, Study 1121, and INNOVATE monotherapy arm) and one randomized controlled trial (INNOVATE) in patients with WM or MZL, including a total n=307 patients overall and n=232 patients exposed to Imbruvica. Study 1118 included 63 patients with previously treated WM who received single agent Imbruvica. Study 1121 included 63 patients with previously treated MZL who received single agent Imbruvica. INNOVATE included 150 patients with treatment naïve or previously treated WM who received Imbruvica or placebo in combination with rituximab. The INNOVATE monotherapy arm included 31 patients with previously treated WM who failed prior rituximab-containing therapy and received Imbruvica.

The most commonly occurring adverse reactions in Studies 1118, 1121, and INNOVATE (≥ 20%) were thrombocytopenia, diarrhea, bruising, neutropenia, musculoskeletal pain, hemorrhage, anemia, rash, fatigue, and nausea.

Seven percent of patients receiving Imbruvica across Studies 1118, 1121, and INNOVATE discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation were atrial fibrillation, interstitial lung disease, diarrhea and rash. Adverse reactions leading to dose reduction occurred in 13% of patients.

Study 1118 and INNOVATE Monotherapy Arm

Adverse reactions and laboratory abnormalities described below in Tables 9 and 10 reflect exposure to Imbruvica with a median duration of 11.7 months in Study 1118 and 33 months in the INNOVATE Monotherapy Arm.

Table 9: Non-Hematologic Adverse Reactions in ≥ 10% in Patients with WM in Study 1118 and the INNOVATE Monotherapy Arm (N=94)
Body System	Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
The body system and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
Gastrointestinal disorders	Diarrhea	38	2
	Nausea	21	0
	Stomatitis*	15	0
	Constipation	12	1
	Gastroesophageal reflux disease	12	0
Skin and subcutaneous tissue disorders	Bruising*	28	1
	Rash*	21	1
Vascular disorders	Hemorrhage*	28	0
	Hypertension*	14	4
General disorders and administrative site conditions	Fatigue	18	2
	Pyrexia	12	2
Musculoskeletal and connective tissue disorders	Musculoskeletal pain*	21	0
	Muscle spasms	19	0
Infections and infestations	Upper respiratory tract infection	19	0
	Skin infection*	18	3
	Sinusitis*	16	0
	Pneumonia*	13	5
Nervous system disorders	Headache	14	0
	Dizziness	13	0
Respiratory, thoracic and mediastinal disorders	Cough	13	0
Table 10: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with WM in Study 1118 and the INNOVATE Monotherapy Arm (N=94)
	Percent of Patients (N=94)
	All Grades (%)	Grade 3 or 4 (%)
Platelets Decreased	38	11
Neutrophils Decreased	43	16
Hemoglobin Decreased	21	6

INNOVATE

Adverse reactions described below in Table 11 reflect exposure to Imbruvica + R with a median duration of 25.8 months and exposure to placebo + R with a median duration of 15.5 months in patients with treatment naïve or previously treated WM in INNOVATE.

Table 11: Adverse Reactions Reported in at Least 10% of Patients and at Least 2% Greater in the Imbruvica Arm in Patients with WM in INNOVATE
Body System Adverse Reaction	Imbruvica + R (N=75)		Placebo + R (N=75)
	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
The body system and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
Skin and subcutaneous tissue disorders
Bruising*	37	1	5	0
Rash*	24	1	11	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	35	4	21	3
Arthralgia	24	3	11	1
Muscle spasms	17	0	12	1
Vascular disorders
Hemorrhage*	32	3	17	3
Hypertension*	20	13	5	4
Gastrointestinal disorders
Diarrhea	28	0	15	1
Nausea	21	0	12	0
Dyspepsia	16	0	1	0
Constipation	13	1	11	1
Infections and infestations
Pneumonia*	19	13	5	3
Skin infection*	17	3	3	0
Urinary tract infection	13	0	0	0
Bronchitis	12	3	7	0
Influenza	12	0	7	1
Viral upper respiratory tract infection	11	0	7	0
General disorders and administration site conditions
Peripheral edema	17	0	12	1
Respiratory, thoracic, and mediastinal disorders
Cough	17	0	11	0
Blood and Lymphatic System Disorders
Neutropenia*	16	12	11	4
Cardiac Disorders
Atrial fibrillation	15	12	3	1
Nervous system disorders
Dizziness	11	0	7	0
Psychiatric disorders
Insomnia	11	0	4	0
Metabolism and nutrition disorders
Hypokalemia	11	0	1	1

Grade 3 or 4 infusion related reactions were observed in 1% of patients treated with Imbruvica + R.

Study 1121

Adverse reactions and laboratory abnormalities described below in Tables 12 and 13 reflect exposure to Imbruvica with a median duration of 11.6 months in Study 1121.

Table 12: Non-Hematologic Adverse Reactions in ≥ 10% in Patients with MZL in Study 1121 (N=63)
Body System	Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
The body system and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
Gastrointestinal disorders	Diarrhea	43	5
	Nausea	25	0
	Dyspepsia	19	0
	Stomatitis*	17	2
	Abdominal pain	16	2
	Constipation	14	0
	Abdominal pain upper	13	0
	Vomiting	11	2
General disorders and administrative site conditions	Fatigue	44	6
	Peripheral edema	24	2
	Pyrexia	17	2
Skin and subcutaneous tissue disorders	Bruising *	41	0
	Rash*	29	5
	Pruritus	14	0
Musculoskeletal and connective tissue disorders	Musculoskeletal pain*	40	3
	Arthralgia	24	2
	Muscle spasms	19	3
Infections and infestations	Upper respiratory tract infection	21	0
	Sinusitis*	19	0
	Bronchitis	11	0
	Pneumonia*	11	10
Metabolism and nutrition disorders	Decreased appetite	16	2
	Hyperuricemia	16	0
	Hypoalbuminemia	14	0
	Hypokalemia	13	0
Vascular disorders	Hemorrhage*	30	0
	Hypertension*	14	5
Respiratory, thoracic and mediastinal disorders	Cough	22	2
	Dyspnea	21	2
Nervous system disorders	Dizziness	19	0
	Headache	13	0
Psychiatric disorders	Anxiety	16	2
Table 13: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with MZL in Study 1121 (N=63)
	Percent of Patients (N=63)
	All Grades (%)	Grade 3 or 4 (%)
Platelets Decreased	49	6
Hemoglobin Decreased	43	13
Neutrophils Decreased	22	13

Chronic Graft versus Host Disease

The data described below reflect exposure to Imbruvica in an open-label clinical trial (Study 1129) that included 42 patients with cGVHD after failure of first line corticosteroid therapy and required additional therapy.

The most commonly occurring adverse reactions in the cGVHD trial (≥ 20%) were fatigue, bruising, diarrhea, thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia. Atrial fibrillation occurred in one patient (2%) which was Grade 3.

Twenty-four percent of patients receiving Imbruvica in the cGVHD trial discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation were fatigue and pneumonia. Adverse reactions leading to dose reduction occurred in 26% of patients.

Adverse reactions and laboratory abnormalities described below in Tables 14 and 15 reflect exposure to Imbruvica with a median duration of 4.4 months in the cGVHD trial.

Table 14: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with cGVHD (N=42)
Body System	Adverse Reaction	All Grades (%)	Grade 3 or 4 (%)
The system organ class and individual ADR preferred terms are sorted in descending frequency order.
* Includes multiple ADR terms.
General disorders and administration site conditions	Fatigue	57	12
	Pyrexia	17	5
	Edema peripheral	12	0
Skin and subcutaneous tissue disorders	Bruising*	40	0
	Rash*	12	0
Gastrointestinal disorders	Diarrhea	36	10
	Stomatitis*	29	2
	Nausea	26	0
	Constipation	12	0
Musculoskeletal and connective tissue disorders	Muscle spasms	29	2
	Musculoskeletal pain*	14	5
Vascular disorders	Hemorrhage*	26	0
Infections and infestations	Pneumonia*	21	10
	Upper respiratory tract infection	19	0
	Sepsis*	10	10
Nervous system disorders	Headache	17	5
Injury, poisoning and procedural complications	Fall	17	0
Respiratory, thoracic and mediastinal disorders	Cough	14	0
	Dyspnea	12	2
Metabolism and nutrition disorders	Hypokalemia	12	7
Table 15: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with cGVHD (N=42)
	Percent of Patients (N=42)
	All Grades (%)	Grade 3 or 4 (%)
Platelets Decreased	33	0
Neutrophils Decreased	10	10
Hemoglobin Decreased	24	2

Additional Important Adverse Reactions

Cardiac Arrhythmias

In randomized controlled trials (n=1377; median treatment duration of 14.0 months for patients treated with Imbruvica and 7.5 months for patients in the control arm), the incidence of ventricular tachyarrhythmias (ventricular extrasystoles, ventricular arrhythmias, ventricular fibrillation, ventricular flutter, and ventricular tachycardia) of any grade was 1.0% versus 0.4% and of Grade 3 or greater was 0.2% versus 0% in patients treated with Imbruvica compared to patients in the control arm. In addition, the incidence of atrial fibrillation and atrial flutter of any grade was 8% versus 2% and for Grade 3 or greater was 4% versus 0.4% in patients treated with Imbruvica compared to patients in the control arm.

Diarrhea

Diarrhea of any grade occurred at a rate of 40% of patients treated with Imbruvica compared to 19% of patients in the control arm. Grade 3 diarrhea occurred in 3% versus 1% of Imbruvica-treated patients compared to the control arm, respectively. The median time to first onset was 21 days (range: 0 to 475) versus 47 days (range: 0 to 492) for any grade diarrhea and 77 days (range: 3 to 310) versus 194 days (range: 11 to 325) for Grade 3 diarrhea in Imbruvica-treated patients compared to the control arm, respectively. Of the patients who reported diarrhea, 84% versus 88% had complete resolution, and 16% versus 12% had not reported resolution at time of analysis in Imbruvica-treated patients compared to the control arm, respectively. The median time from onset to resolution in Imbruvica-treated subjects was 6 days (range: 1 to 655) versus 5 days (range: 1 to 367) for any grade diarrhea and 6 days (range: 1 to 78) versus 19 days (range: 1 to 56) for Grade 3 diarrhea in Imbruvica-treated subjects compared to the control arm, respectively. Less than 1% of subjects discontinued Imbruvica due to diarrhea compared with 0% in the control arm.

Visual Disturbance

Blurred vision and decreased visual acuity of any grade occurred in 12% of patients treated with Imbruvica (10% Grade 1, 2% Grade 2, no Grade 3 or higher) compared to 6% in the control arm (5% Grade 1 and <1% Grade 2 and 3). The median time to first onset was 96 days (range, 0 to 617) versus 109 days (range, 2 to 477) in Imbruvica-treated patients compared to the control arm, respectively. Of the patients who reported visual disturbances, 61% versus 71% had complete resolution and 39% versus 29% had not reported resolution at the time of analysis in Imbruvica-treated patients compared to the control arm, respectively. The median time from onset to resolution was 31 days (range, 1 to 457) versus 29 days (range, 1 to 253) in Imbruvica-treated subjects compared to the control arm, respectively.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Imbruvica. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

· Hepatobiliary disorders: hepatic failure including acute and/or fatal events, hepatic cirrhosis

· Respiratory disorders: interstitial lung disease

· Metabolic and nutrition disorders: tumor lysis syndrome [see Warnings & Precautions (5.7)]

· Immune system disorders: anaphylactic shock, angioedema, urticaria

· Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis, panniculitis

· Infections: hepatitis B reactivation

Drug InteractionsEffect 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 (2.4)].

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 (2.4)].

Avoid grapefruit and Seville oranges during Imbruvica treatment, as these contain strong or moderate inhibitors of CYP3A.

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)].

USE IN SPECIFIC POPULATIONSPregnancy

Risk Summary

Imbruvica, a kinase inhibitor, 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 2-20 times the clinical doses of 420-560 mg daily produced embryofetal toxicity including structural abnormalities (see Data). 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.

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 14 times the exposure (AUC) in patients with MCL or MZL and 20 times the exposure in patients with CLL/SLL or WM 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 rats is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 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 2.0 times the exposure (AUC) in patients with MCL and 2.8 times the exposure in patients with CLL/SLL or WM administered the dose of 560 and 420 mg daily, respectively.

Lactation

Risk Summary

There is no information regarding the presence of ibrutinib or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production.

The development and health benefits of breastfeeding should be considered along with the mother's clinical need for Imbruvica and any potential adverse effects on the breastfed child from Imbruvica or from the underlying maternal condition.

Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Imbruvica therapy.

Contraception

Females

Advise females of reproductive potential to avoid pregnancy while taking Imbruvica and for up to 1 month after ending treatment. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus.

Males

Advise men to avoid fathering a child while receiving Imbruvica, and for 1 month following the last dose of Imbruvica.

Pediatric Use

The safety and effectiveness of Imbruvica in pediatric patients has not been established. Pediatric studies have not been completed.

Geriatric Use

Of the 1011 patients in clinical studies of Imbruvica, 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) and Grade 3 or higher pneumonia occurred more frequently among older patients treated with Imbruvica.

Hepatic Impairment

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.

Dose modifications of Imbruvica are recommended in patients with mild or moderate hepatic impairment (Child-Pugh class A and B). Monitor patients for adverse reactions of Imbruvica closely [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

Plasmapheresis

Management of hyperviscosity in WM patients may include plasmapheresis before and during treatment with Imbruvica. Modifications to Imbruvica dosing are not required.

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.

Imbruvica 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:

 

Imbruvica (ibrutinib) is available as immediate-release oral capsules and immediate-release oral tablets.

Imbruvica (ibrutinib) capsules for oral administration 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 administration are available in the following dosage strengths: 140 mg, 280 mg, 420 mg, and 560 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 and 560 mg tablets), talc, titanium dioxide, and yellow iron oxide (140 mg, 420 mg, and 560 mg tablets).

Imbruvica - Clinical PharmacologyMechanism 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.

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).

In vitro Platelet Aggregation

Ibrutinib demonstrated inhibition of collagen-induced platelet aggregation, with IC50 values at 4.6 μM (2026 ng/mL), 0.8 μM (352 ng/mL), and 3 μM (1321 ng/mL) in blood samples from healthy donors, donors taking warfarin, and donors with severe renal dysfunction, respectively. Ibrutinib did not show meaningful inhibition of platelet aggregation for ADP, arachidonic acid, ristocetin, and TRAP-6.

Cardiac Electrophysiology

At a single dose 3 times the maximum recommended dose (1680 mg), Imbruvica did not prolong the QT interval to any clinically relevant extent.

Pharmacokinetics

Ibrutinib exposure increases with doses up to 840 mg (1.5 times the maximum approved recommended dosage) in patients with B-cell malignancies. The mean steady-state AUC (% coefficient of variation) observed in patients at 560 mg with MCL is 865 (69%) ng∙h/mL and with MZL is 978 (82%) ng∙h/mL, and in patients at 420 mg with CLL/SLL is 708 (71%) ng∙h/mL, with WM is 707 (72%) ng∙h/mL, and with cGVHD is 1159 (50%) ng∙h/mL. Steady-state concentrations of ibrutinib without CYP3A inhibitors were achieved with an accumulation ratio of 1 to 1.6 after 1 week of multiple daily doses of 420 mg or 560 mg.

Absorption

Absolute bioavailability of ibrutinib in fasted condition was 2.9% (90% CI: 2.1, 3.9) in healthy subjects. Ibrutinib is absorbed after oral administration with a median Tmax of 1 hour to 2 hours.

Effect of Food

The administration of Imbruvica with a high-fat and high-calorie meal (800 calories to 1,000 calories with approximately 50% of total caloric content of the meal from fat) increased ibrutinib Cmax by 2- to 4-fold and AUC by approximately 2-fold, compared with administration of ibrutinib after overnight fasting.

In vitro studies suggest that ibrutinib is not a substrate of p-glycoprotein (P-gp) or breast cancer resistance protein (BCRP).

Distribution

Reversible binding of ibrutinib to human plasma protein in vitro was 97.3% with no concentration dependence in the range of 50 ng/mL to 1000 ng/mL. The volume of distribution (Vd) was 683 L, and the apparent volume of distribution at steady state (Vd,ss/F) was approximately 10,000 L.

Elimination

Intravenous clearance was 62 L/h in fasted conditions and 76 L/h in fed conditions. In line with the high first-pass effect, the apparent oral clearance is 2000 L/h in fasted conditions and 1000 L/h in fed conditions. The half-life of ibrutinib is 4 hours to 6 hours.

Metabolism

Metabolism is the main route of elimination for ibrutinib. It is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A 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.

Excretion

Ibrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After a single oral administration of radiolabeled ibrutinib, 90% of radioactivity was excreted within 168 hours, with 80% excreted in the feces and less than 10% eliminated in urine. Unchanged ibrutinib accounted for 1% of the radiolabeled excreted dose in feces and none in urine, with the remainder of the excreted dose being metabolites.

Specific Populations

Age and Sex

Age and sex have no clinically meaningful effect on ibrutinib pharmacokinetics.

Patients with Renal Impairment

Mild and moderate renal impairment (creatinine clearance [CLcr] > 25 mL/min as estimated by Cockcroft-Gault equation) had no influence on the exposure of ibrutinib. No data is available in patients with severe renal impairment (CLcr < 25 mL/min) or in patients on dialysis.

Patients with Hepatic Impairment

The AUC of ibrutinib increased 2.7-fold in subjects with mild hepatic impairment (Child-Pugh class A), 8.2-fold in subjects with moderate hepatic impairment (Child-Pugh class B) and 9.8-fold in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function. The Cmax of ibrutinib increased 5.2-fold in mild hepatic impairment, 8.8-fold in moderate hepatic impairment and 7-fold in severe hepatic impairment relative to subjects with normal liver function [see Use in Specific Populations (8.6)].

Drug Interaction Studies

Effect of CYP3A Inhibitors on Ibrutinib

The coadministration of multiple doses of ketoconazole (strong CYP3A inhibitor) increased the Cmax of ibrutinib by 29-fold and AUC by 24-fold. The coadministration of multiple doses of voriconazole (strong CYP3A inhibitor) increased steady state Cmax of ibrutinib by 6.7-fold and AUC by 5.7-fold. Simulations under fed conditions suggest that posaconazole (strong CYP3A inhibitor) may increase the AUC of ibrutinib 3-fold to 10-fold.

The coadministration of multiple doses of erythromycin (moderate CYP3A inhibitor) increased steady state Cmax of ibrutinib by 3.4-fold and AUC by 3-fold.

Effect of CYP3A Inducers on Ibrutinib

The coadministration of rifampin (strong CYP3A inducer) decreased the Cmax of ibrutinib by more than 13-fold and AUC by more than 10-fold. Simulations suggest that efavirenz (moderate CYP3A inducer) may decrease the AUC of ibrutinib by 3-fold.

Effect of Ibrutinib on CYP Substrates

In vitro studies suggest that ibrutinib and PCI-45227 are unlikely to inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A at clinical doses. Both ibrutinib and PCI-45227 are unlikely to induce CYP1A2, CYP2B6 or CYP3A at clinical doses.

Effect of Ibrutinib on Substrates of Transporters

In vitro studies suggest that ibrutinib may inhibit BCRP and P-gp transport at clinical doses. The coadministration of oral P-gp or BCRP substrates with a narrow therapeutic index (e.g., digoxin, methotrexate) with Imbruvica may increase their concentrations.

Nonclinical ToxicologyCarcinogenesis, Mutagenesis, Impairment of Fertility

Ibrutinib was not carcinogenic in a 6-month rasH2 mouse study at oral doses up to 2000 mg/kg/day resulting in exposures approximately 23 (males) to 37 (females) times higher than the exposure in humans at a dose of 560 mg daily [see Warnings and Precautions (5.6)].

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.

Rats were administered oral daily doses of ibrutinib for 4 weeks prior to pairing and during pairing in males and 2 weeks prior to pairing and during pairing in females. Treatment of female rats continued following pregnancy up to gestation day (GD) 7, and treatment of male rats continued until end of study. No effects on fertility or reproductive capacities were observed in male or female rats up to the maximum dose tested, 100 mg/kg/day (Human Equivalent Dose [HED] 16 mg/kg).

Clinical StudiesMantle Cell Lymphoma

The safety and efficacy of Imbruvica in patients with MCL who have received at least one prior therapy were evaluated in Study PCYC-1104-CA (referred to as Study 1104) (NCT01236391), 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 transplantation. 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 16.

Table 16: Overall Response Rate (ORR) and Duration of Response (DOR) Based on Investigator Assessment in Patients with MCL in Study 1104
	Total (N=111)
CI = confidence interval; CR = complete response; PR = partial response; NE = not evaluable
ORR (%)	65.8
95% CI (%)	(56.2, 74.5)
CR (%)	17.1
PR (%)	48.6
Median DOR months (95% CI)	17.5 (15.8, NE)

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.

Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

The safety and efficacy of Imbruvica in patients with CLL/SLL were demonstrated in one uncontrolled trial and three randomized, controlled trials.

Study 1102

Study PCYC-1102-CA (referred to as Study 1102) (NCT01105247), an open-label, multi-center trial, was conducted in 48 previously treated CLL 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.

RESONATE

The RESONATE study (A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib versus Ofatumumab in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma) (NCT01578707) was conducted in patients with previously treated CLL or SLL. Patients (n=391) were randomized 1:1 to receive either Imbruvica 420 mg daily until disease progression, or unacceptable toxicity or ofatumumab at an initial dose of 300 mg, followed one week later by a dose of 2000 mg weekly for 7 doses and then every 4 weeks for 4 additional doses. Fifty seven patients randomized to ofatumumab crossed over following progression to receive Imbruvica. The median age was 67 years (range, 30 to 88 years), 68% were male, and 90% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The trial enrolled 373 patients with CLL and 18 patients with SLL. The median time since diagnosis was 91 months and the median number of prior treatments was 2 (range, 1 to 13 treatments). At baseline, 58% of patients had at least one tumor ≥ 5 cm. Thirty-two percent of patients had 17p deletion.

Efficacy results for RESONATE are shown in Table 17 and the Kaplan-Meier curves for PFS, assessed by an IRC according to IWCLL criteria, and OS are shown in Figures 1 and 2, respectively.

Table 17: Efficacy Results in Patients with CLL/SLL in RESONATE
Endpoint	Imbruvica N=195	Ofatumumab N=196
a Median OS not evaluable for either arm b IRC evaluated. All partial responses achieved; none of the patients achieved a complete response. CI = confidence interval; HR = hazard ratio; NE = not evaluable
Progression Free Survivalb
Number of events (%)	35 (17.9)	111 (56.6)
Disease progression	26	93
Death events	9	18
Median (95% CI), months	NE	8.1 (7.2, 8.3)
HR (95% CI)	0.22 (0.15, 0.32)
Overall Survivala
Number of deaths (%)	16 (8.2)	33 (16.8)
HR (95% CI)	0.43 (0.24, 0.79)
Overall Response Rateb	42.6%	4.1%

Figure 1: Kaplan-Meier Curve of Progression Free Survival (ITT Population) in Patients with CLL/SLL in RESONATE

 

Figure 2: Kaplan-Meier Curve of Overall Survival (ITT Population) in Patients with CLL/SLL in RESONATE

 

CLL/SLL with 17p deletion (del 17p CLL/SLL) in RESONATE

RESONATE included 127 patients with del 17p CLL/SLL. The median age was 67 years (range, 30 to 84 years), 62% were male, and 88% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. PFS and ORR were assessed by an IRC. Efficacy results for del 17p CLL/SLL are shown in Table 18.

Table 18: Efficacy Results in Patients with del 17p CLL/SLL in RESONATE
Endpoint	Imbruvica N=63	Ofatumumab N=64
a IRC evaluated. All partial responses achieved; none of the patients achieved a complete response. CI = confidence interval; HR = hazard ratio; NE = not evaluable
Progression Free Survivala
Number of events (%)	16 (25.4)	38 (59.4)
Disease progression	12	31
Death events	4	7
Median (95% CI), months	NE	5.8 (5.3, 7.9)
HR (95% CI)	0.25 (0.14, 0.45)
Overall Response Ratea	47.6%	4.7%

RESONATE-2

The RESONATE-2 study (A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 versus Chlorambucil in Patients 65 Years or Older with Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma) (NCT01722487) was conducted in patients with treatment naïve CLL or SLL who were 65 years of age or older. Patients (n = 269) were randomized 1:1 to receive either Imbruvica 420 mg daily until disease progression or unacceptable toxicity, or chlorambucil at a starting dose of 0.5 mg/kg on Days 1 and 15 of each 28-day cycle for a maximum of 12 cycles, with an allowance for intrapatient dose increases up to 0.8 mg/kg based on tolerability.

The median age was 73 years (range, 65 to 90 years), 63% were male, and 91% were Caucasian. Ninety one percent of patients had a baseline ECOG performance status of 0 or 1 and 9% had an ECOG performance status of 2. The trial enrolled 249 patients with CLL and 20 patients with SLL. At baseline, 20% of patients had 11q deletion. The most common reasons for initiating CLL therapy include: progressive marrow failure demonstrated by anemia and/or thrombocytopenia (38%), progressive or symptomatic lymphadenopathy (37%), progressive or symptomatic splenomegaly (30%), fatigue (27%) and night sweats (25%).

With a median follow-up of 28.1 months, there were 32 observed death events [11 (8.1%) and 21 (15.8%) in Imbruvica and chlorambucil treatment arms, respectively]. With 41% of patients switching from chlorambucil to Imbruvica, the overall survival analysis in the ITT patient population resulted in a statistically significant HR of 0.44 [95% CI (0.21, 0.92)] and 2-year survival rate estimates of 94.7% [95% CI (89.1, 97.4)] and 84.3% [95% CI (76.7, 89.6)] in the Imbruvica and chlorambucil arms, respectively.

Efficacy results for RESONATE-2 are shown in Table 19 and the Kaplan-Meier curve for PFS, assessed by an IRC according to IWCLL criteria is shown in Figure 3.

Table 19: Efficacy Results in Patients with CLL/SLL in RESONATE-2
Endpoint	Imbruvica N=136	Chlorambucil N=133
a IRC evaluated; Five subjects (3.7%) in the Imbruvica arm and two subjects (1.5%) in the Chlorambucil arm achieved complete response b HR = hazard ratio; NE = not evaluable
Progression Free Survivala
Number of events (%)	15 (11.0)	64 (48.1)
Disease progression	12	57
Death events	3	7
Median (95% CI), months	NE	18.9 (14.1, 22.0)
HRb (95% CI)	0.16 (0.09, 0.28)
Overall Response Ratea (CR + PR)	82.4%	35.3%
P-value	<0.0001

Figure 3: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients with CLL/SLL in RESONATE-2

 

HELIOS

The HELIOS study (Randomized, Double-blind, Placebo-controlled Phase 3 Study of Ibrutinib, a Bruton's Tyrosine Kinase (BTK) Inhibitor, in Combination with Bendamustine and Rituximab (BR) in Subjects with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma) (NCT01611090) was conducted in patients with previously treated CLL or SLL. Patients (n = 578) were randomized 1:1 to receive either Imbruvica 420 mg daily or placebo in combination with BR until disease progression, or unacceptable toxicity. All patients received BR for a maximum of six 28-day cycles. Bendamustine was dosed at 70 mg/m2 infused IV over 30 minutes on Cycle 1, Days 2 and 3, and on Cycles 2-6, Days 1 and 2 for up to 6 cycles. Rituximab was administered at a dose of 375 mg/m2 in the first cycle, Day 1, and 500 mg/m2 Cycles 2 through 6, Day 1.

The median age was 64 years (range, 31 to 86 years), 66% were male, and 91% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 5.9 years and the median number of prior treatments was 2 (range, 1 to 11 treatments). At baseline, 56% of patients had at least one tumor ≥ 5 cm and 26% presented with del11q.

Efficacy results for HELIOS are shown in Table 20 and the Kaplan-Meier curves for PFS are shown in Figure 4.

Table 20: Efficacy Results in Patients with CLL/SLL in HELIOS
Endpoint	Imbruvica + BR N=289	Placebo + BR N=289
a IRC evaluated, twenty-four subjects (8.3%) in the Imbruvica + BR arm and six subjects (2.1%) in the placebo + BR arm achieved complete response BR = bendamustine and rituximab; CI = confidence interval; HR = hazard ratio; NE = not evaluable
Progression Free Survivala
Number of events (%)	56 (19.4)	183 (63.3)
Median (95% CI), months	NE	13.3 (11.3, 13.9)
HR (95% CI)	0.20 (0.15, 0.28)
Overall Response Ratea	82.7%	67.8%

Figure 4: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients with CLL/SLL in HELIOS

 

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 66% of patients in the CLL studies. The onset of isolated lymphocytosis occurs during the first month of Imbruvica therapy and resolves by a median of 14 weeks (range, 0.1 to 104 weeks). When Imbruvica was administered with chemoimmunotherapy, lymphocytosis was 7% with Imbruvica + BR versus 6% with placebo + BR.

Waldenström's Macroglobulinemia

The safety and efficacy of Imbruvica in patients with WM were demonstrated in two single-arm trials and one randomized, controlled trial.

Study 1118 and INNOVATE Monotherapy Arm

The safety and efficacy of Imbruvica in WM were evaluated in Study PCYC-1118E (referred to as Study 1118) (NCT01614821), an open-label, multi-center, single-arm trial of 63 previously treated patients. The median age was 63 years (range, 44 to 86 years), 76% were male, and 95% were Caucasian. All patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 74 months, and the median number of prior treatments was 2 (range, 1 to 11 treatments). At baseline, the median serum IgM value was 3.5 g/dL (range, 0.7 to 8.4 g/dL).

Imbruvica was administered orally at 420 mg once daily until disease progression or unacceptable toxicity. The responses were assessed by investigators and an IRC using criteria adopted from the International Workshop of Waldenström's Macroglobulinemia. Responses, defined as partial response or better, per IRC are shown in Table 21.

Table 21: Response Rate and Duration of Response (DOR) Based on IRC Assessment in Patients with WM in Study 1118
	Total (N=63)
CI = confidence interval; NE = not evaluable
Response rate (CR+VGPR+PR), (%)	61.9
95% CI (%)	(48.8, 73.9)
Complete Response (CR)	0
Very Good Partial Response (VGPR), (%)	11.1
Partial Response (PR), (%)	50.8
Median duration of response, months (range)	NE (2.8+, 18.8+)

The median time to response was 1.2 months (range, 0.7-13.4 months).

The INNOVATE monotherapy arm included 31 patients with previously treated WM who failed prior rituximab-containing therapy and received single-agent Imbruvica. The median age was 67 years (range, 47 to 90 years). Eighty-one percent of patients had a baseline ECOG performance status of 0 or 1, and 19% had a baseline ECOG performance status of 2. The median number of prior treatments was 4 (range, 1 to 7 treatments). The response rate observed in the INNOVATE monotherapy arm was 71% (0% CR, 29% VGPR, 42% PR). With a median follow-up time on study of 34 months (range, 8.6+ to 37.7 months), the median duration of response has not been reached.

INNOVATE

The INNOVATE study (A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Ibrutinib or Placebo in Combination with Rituximab in Subjects with Waldenström's Macroglobulinemia) (NCT02165397) was conducted in treatment naïve or previously treated patients with WM. Patients (n = 150) were randomized 1:1 to receive either Imbruvica 420 mg daily or placebo in combination with rituximab until disease progression or unacceptable toxicity. Rituximab was administered weekly at a dose of 375 mg/m2 for 4 consecutive weeks (weeks 1-4) followed by a second course of weekly rituximab for 4 consecutive weeks (weeks 17-20). The major efficacy outcome measure is progression-free survival (PFS) assessed by an IRC with additional efficacy measure of response rate.

The median age was 69 years (range, 36 to 89 years), 66% were male, and 79% were Caucasian. Ninety-three percent of patients had a baseline ECOG performance status of 0 or 1, and 7% of patients had a baseline ECOG performance status of 2. Forty-five percent of patients were treatment naïve, and 55% of patients were previously treated. Among previously treated patients, the median number of prior treatments was 2 (range, 1 to 6 treatments). At baseline, the median serum IgM value was 3.2 g/dL (range, 0.6 to 8.3 g/dL), and MYD88 L265P mutations were present in 77% of patients, absent in 13% of patients, and 9% of patients were not evaluable for mutation status.

Efficacy results for INNOVATE as assessed by an IRC are shown in Table 22, and the Kaplan-Meier curves for PFS are shown in Figure 5.

Table 22: Efficacy Results in Patients with WM in INNOVATE
Endpoint	Imbruvica + R N=75	Placebo + R N=75
CI = confidence interval; HR = hazard ratio; NE = not evaluable; R = rituximab
* P-value is from log-rank test stratified by WM IPSS (low, med, high) and number of prior systemic treatment regimens (0, ≥1) † P-value associated with response rate was <0.0001. Median follow-up time on study = 26.5 months
Progression Free Survival
Number of events (%)	14 (19)	42 (56)
Median (95% CI), months	NE	20.3 (13.7, 27.6)
HR (95% CI)	0.20 (0.11, 0.38)
P-value*	<0.0001
Response Rate (CR+VGPR+PR)†	72%	32%
95% CI	(0.62, 0.82)	(0.21, 0.43)
Complete Response (CR)	3%	1%
Very Good Partial Response (VGPR)	23%	4%
Partial Response (PR)	47%	27%
Median duration of response, months (range)	NE (1.9+, 36.4+)	21.2 (4.6, 25.8)
Figure 5: Kaplan-Meier Curve of Progression-Free Survival (ITT Population) in Patients with WM in INNOVATE

An exploratory analysis demonstrated a sustained hemoglobin improvement (defined as increase of ≥ 2 g/dL over baseline for at least 8 weeks without blood transfusions or growth factor support) in 65% of patients in the Imbruvica + R group and 39% of patients in the placebo + R group.

Marginal Zone Lymphoma

The safety and efficacy of Imbruvica in MZL were evaluated in Study PCYC-1121-CA (referred to as Study 1121) (NCT01980628), an open-label, multi-center, single-arm trial of patients who received at least one prior therapy. The efficacy analysis included 63 patients with 3 sub-types of MZL: mucosa-associated lymphoid tissue (MALT; N=32), nodal (N=17), and splenic (N=14). The median age was 66 years (range, 30 to 92 years), 59% were female, and 84% were Caucasian. Ninety two percent of patients had a baseline ECOG performance status of 0 or 1 and 8% had ECOG performance status 2. The median time since diagnosis was 3.8 years, and the median number of prior treatments was 2 (range, 1 to 9 treatments).

Imbruvica was administered orally at 560 mg once daily until disease progression or unacceptable toxicity. The responses were assessed by investigators and an IRC using criteria adopted from the International Working Group criteria for malignant lymphoma. Responses per IRC are shown in Table 23.

Table 23: Overall Response Rate (ORR) and Duration of Response (DOR) Based on IRC Assessment in Patients with MZL in Study 1121
	Total (N=63)
CI = confidence interval; NE = not evaluable Median follow-up time on study = 19.4 months
Response rate (CR + PR), (%)	46.0%
95% CI (%)	(33.4, 59.1)
Complete Response (CR), (%)	3.2
Partial Response (PR), (%)	42.9
Median duration of response, months (range)	NE (16.7, NE)

The median time to response was 4.5 months (range, 2.3 to 16.4 months). Overall response rates were 46.9%, 41.2%, and 50.0% for the 3 MZL sub-types (MALT, nodal, splenic), respectively.

Chronic Graft versus Host Disease

The safety and efficacy of Imbruvica in cGVHD were evaluated in Study PCYC-1129-CA (referred to as Study 1129) (NCT02195869), an open-label, multi-center, single-arm trial of 42 patients with cGVHD after failure of first line corticosteroid therapy and requiring additional therapy. The median age was 56 years (range, 19 to 74 years), 52% were male, and 93% were Caucasian. The most common underlying malignancies leading to transplantation were acute lymphocytic leukemia, acute myeloid leukemia, and CLL. The median time since cGVHD diagnosis was 14 months, the median number of prior cGVHD treatments was 2 (range, 1 to 3 treatments), and 60% of patients had a Karnofsky performance score of ≤ 80. The majority of patients (88 %) had at least 2 organs involved at baseline, with the most commonly involved organs being mouth (86%), skin (81%), and gastrointestinal tract (33%). The median daily corticosteroid dose (prednisone or prednisone equivalent) at baseline was 0.3 mg/kg/day, and 52% of patients were receiving ongoing immunosuppressants in addition to systemic corticosteroids at baseline. Prophylaxis for infections were managed per institutional guidelines with 79% of patients receiving combinations of sulfonamides and trimethoprim and 64% receiving triazole derivatives.

Imbruvica was administered orally at 420 mg once daily. The responses were assessed by investigators using the 2005 National Institute of Health (NIH) Consensus Panel Response Criteria with two modifications to align with the updated 2014 NIH Consensus Panel Response Criteria. Efficacy results are shown in Table 24.

Table 24: Best Overall Response Rate (ORR) and Sustained Response Rate Based on Investigator Assessmenta in Patients with cGVHD in Study 1129
	Total (N=42)
CI = confidence interval a Investigator assessment based on the 2005 NIH Response Criteria with two modifications (added "not evaluable" for organs with non-cGVHD abnormalities, and organ score change from 0 to 1 was not considered disease progression) b Sustained response rate is defined as the proportion of patients who achieved a CR or PR that was sustained for at least 20 weeks.
ORR	28 (67%)
95% CI	(51%, 80%)
Complete Response (CR)	9 (21%)
Partial Response (PR)	19 (45%)
Sustained response rateb	20 (48%)

The median time to response coinciding with the first scheduled response assessment was 12.3 weeks (range, 4.1 to 42.1 weeks). Responses were seen across all organs involved for cGVHD (skin, mouth, gastrointestinal tract, and liver).

ORR results were supported by exploratory analyses of patient-reported symptom bother which showed at least a 7-point decrease in Lee Symptom Scale overall summary score in 24% (10/42) of patients on at least 2 consecutive visits.

How Supplied/Storage and Handling

The 70 mg capsules are supplied as yellow opaque capsules, marked with "ibr 70 mg" in black ink, and are available 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, and 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 until dispensing.

The Imbruvica (ibrutinib) tablets are supplied in 4 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

· 560 mg tablets: Yellow to orange oblong tablets debossed with "ibr" on one side and "560" on the other side. Carton of one folded blister card containing two 14-count blister strips for a total of 28 tablets: NDC 57962-560-28

Store tablets in original packaging 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).

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

· Hemorrhage:
Inform patients of the possibility of bleeding, and to report any signs or symptoms (severe headache, 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, weakness, confusion) suggestive of infection [see Warnings and Precautions (5.2)].

· Cardiac Arrhythmias:
Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions (5.4)].

· Hypertension:
Inform patients that high blood pressure has occurred in patients taking Imbruvica, which may require treatment with anti-hypertensive therapy [see Warnings and Precautions (5.5].

· 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 (5.6)].

· Tumor lysis syndrome:
Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions (5.7)].

· Embryo-fetal toxicity:
Advise women of the potential hazard to a fetus and to avoid becoming pregnant during treatment and for 1 month after the last dose of Imbruvica [see Warnings and Precautions (5.8)].

· Inform patients to take Imbruvica orally once daily according to their physician's instructions and that the oral dosage (capsules or tablets) should be swallowed whole with a glass of water without opening, breaking or chewing the capsules or cutting, crushing or chewing the tablets 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 doses to make up the missed dose [see Dosage and Administration (2.6)].

· 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. Advise patients to maintain adequate hydration [see Adverse Reactions (6.1)].

 

 

 

Active ingredient made in China.

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

Patent http://www.Imbruvica.com
Imbruvica® is a registered trademark owned by Pharmacyclics LLC

© Pharmacyclics LLC 2018
© Janssen Biotech, Inc. 2018

Patient Information
Imbruvica (im-BRU-vih-kuh) (ibrutinib) capsules		Imbruvica (im-BRU-vih-kuh) (ibrutinib) tablets
What is Imbruvica? Imbruvica is a prescription medicine used to treat adults with: · Mantle cell lymphoma (MCL) who have received at least one prior treatment · Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) · Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion · Waldenström's macroglobulinemia (WM) · Marginal zone lymphoma (MZL) who require a medicine by mouth or injection (systemic therapy) and have received a certain type of prior treatment · Chronic graft versus host disease (cGVHD) after failure of 1 or more lines of systemic therapy It is not known if Imbruvica is safe and effective in children.
Before taking 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 or had heart rhythm problems, smoke, or have a medical condition that increases your risk of heart disease, such as high blood pressure, high cholesterol, or diabetes · have an infection · have liver problems · are pregnant or plan to become pregnant. Imbruvica can harm your unborn baby. If you are able to become pregnant, your healthcare provider will do a pregnancy test before starting treatment with Imbruvica. o Females should not become pregnant during treatment and for 1 month after the last dose of Imbruvica. o Males should avoid getting female partners pregnant during treatment and for 1 month after the last dose of Imbruvica. · are breastfeeding or plan to breastfeed. You and your healthcare provider should decide if you will take Imbruvica or breastfeed. 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 and tablets whole with a glass of water. · Do not open, break, or chew Imbruvica capsules. · Do not cut, crush, or chew Imbruvica tablets. · 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 extra doses of Imbruvica to make up for a missed dose. · If you take too much Imbruvica call your healthcare provider or go to the nearest hospital emergency room right away.
What should I avoid while taking Imbruvica? · You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) during treatment with 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 (hemorrhage) are common during treatment with Imbruvica, and can also be serious and may lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. 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 cannot control · vomit blood or vomit looks like coffee grounds · cough up blood or blood clots		· increased bruising · dizziness · weakness · confusion · change in your speech · headache that lasts a long time
· Infections can happen during treatment with Imbruvica. These infections can be serious and may lead to death. Tell your healthcare provider right away if you have fever, chills, weakness, confusion, or other signs or symptoms of an infection during treatment with Imbruvica. · Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with Imbruvica, but can also be severe. Your healthcare provider should do monthly blood tests to check your blood counts. · Heart rhythm problems (ventricular arrhythmias, atrial fibrillation and atrial flutter). Serious heart rhythm problems and death have happened in people treated with Imbruvica, especially in people who have an increased risk for heart disease, have an infection, or who have had heart rhythm problems in the past. Tell your healthcare provider if you get any symptoms of heart rhythm problems, such as feeling as if your heart is beating fast and irregular, lightheadedness, dizziness, shortness of breath, chest discomfort, or you faint. · High blood pressure (hypertension). New or worsening high blood pressure has happened in people treated with Imbruvica. Your healthcare provider may start you on blood pressure medicine or change current medicines to treat your blood pressure. · Second primary cancers: New cancers have happened during treatment with Imbruvica, including cancers of the skin or other organs. · Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS. The most common side effects of Imbruvica in adults with B-cell malignancies (MCL, CLL/SLL, WM and MZL) include:
	· diarrhea · muscle and bone pain · rash · nausea	· bruising · tiredness · fever
The most common side effects of Imbruvica in adults with cGVHD include:
	· tiredness · bruising · diarrhea	· mouth sores (stomatitis) · muscle spasms · nausea		· pneumonia
Diarrhea is a common side effect in people who take Imbruvica. Drink plenty of fluids during treatment with Imbruvica to help reduce your risk of losing too much fluid (dehydration) due to diarrhea. 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 capsules at room temperature between 68°F to 77°F (20°C to 25°C). · Keep Imbruvica capsules in the original container with the lid tightly closed. · Store Imbruvica tablets at room temperature between 68°F to 77°F (20°C to 25°C). · Keep Imbruvica tablets in the original carton. 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: Imbruvica capsules: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The 70 mg capsule shell contains gelatin, titanium dioxide, yellow iron oxide, and black ink. The 140 mg capsule shell contains gelatin, titanium dioxide, and black ink. Imbruvica tablets: 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 and 560 mg tablets), talc, titanium dioxide, and yellow iron oxide (140 mg, 420 mg, and 560 mg tablets). Distributed and Marketed by: Pharmacyclics LLC Sunnyvale, CA USA 94085 Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044. © Pharmacyclics LLC 2018 © Janssen Biotech, Inc. 2018 For more information, go to www.Imbruvica.com or call 1-877-877-3536.
This Patient Information has been approved by the U.S. Food and Drug Administration.				Revised: 08/2018

PRINCIPAL DISPLAY PANEL - 28 Capsule Bottle Carton

NDC 57962-070-28

Imbruvica®
(ibrutinib) capsules

70 mg

Each capsule contains: ibrutinib 70 mg
Swallow capsules whole with water

28 Capsules

Rx Only

Pharmacyclics LLC
An AbbVie Company

Janssen Biotech, Inc.

 

PRINCIPAL DISPLAY PANEL - 28 Capsule Bottle Label

NDC 57962-070-28

Imbruvica®
(ibrutinib) capsules

70 mg

Each capsule contains: ibrutinib 70 mg
Swallow capsules whole with water

28 Capsules

Rx Only

Pharmacyclics LLC
An AbbVie Company

Janssen Biotech, Inc.

 

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 LLC
An AbbVie Company

Janssen Biotech, Inc.

 

PRINCIPAL DISPLAY PANEL - 120 Capsule Bottle Carton

NDC 57962-140-12

Imbruvica®
(ibrutinib) capsules

140 mg

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

120 Capsules

Rx Only

Pharmacyclics LLC
An AbbVie Company

Janssen Biotech, Inc.

 

PRINCIPAL DISPLAY PANEL - 28 Tablet Blister Carton

NDC 57962-014-28

Imbruvica®
(ibrutinib) tablets

140 mg

Each table contains: ibrutinib 140 mg
Swallow tablet whole with water

28 Tablets

Rx Only

Pharmacyclics LLC
An AbbVie Company

Janssen Biotech, Inc.

 

PRINCIPAL DISPLAY PANEL - 28 Tablet Blister Strip (Front)

NDC 57962-014-28

Imbruvica®
(ibrutinib) tablets

140 mg

Each table contains: ibrutinib 140 mg
Swallow tablet whole with water

28 Tablets

Rx Only

Pharmacyclics LLC
An AbbVie Company

Janssen Biotech, Inc.

 

PRINCIPAL DISPLAY PANEL - 28 Tablet Blister Strip (Back)

NDC 57962-014-28

Imbruvica®
(ibrutinib) tablets

140 mg

Each table contains: ibrutinib 140 mg
Swallow tablet whole with water

28 Tablets

Rx Only

Pharmacyclics LLC
An AbbVie Company

Janssen Biotech, Inc.

 

PRINCIPAL DISPLAY PANEL - 28 Tablet Blister Carton

NDC 57962-280-28

Imbruvica®
(ibrutinib) tablets

280 mg

Each table contains: ibrutinib 280 mg
Swallow tablet whole with water

28 Tablets

Rx Only

Pharmacyclics LLC
An AbbVie Company

Janssen Biotech, Inc.

 

PRINCIPAL DISPLAY PANEL - 28 Tablet Blister Strip (Front)

NDC 57962-280-28

Imbruvica®
(ibrutinib) tablets

280 mg

Each table contains: ibrutinib 280 mg
Swallow tablet whole with water

28 Tablets

Rx Only

Pharmacyclics LLC
An AbbVie Company

Janssen Biotech, Inc.

 

PRINCIPAL DISPLAY PANEL - 28 Tablet Blister Strip (Back)

NDC 57962-280-28

Imbruvica®
(ibrutinib) tablets

280 mg

Each table contains: ibrutinib 280 mg
Swallow tablet whole with water

28 Tablets

Rx Only

Pharmacyclics LLC
An AbbVie Company

Janssen Biotech, Inc.

 

PRINCIPAL DISPLAY PANEL - 28 Tablet Blister Carton

NDC 57962-420-28

Imbruvica®
(ibrutinib) tablets

420 mg

Each table contains: ibrutinib 420 mg
Swallow tablet whole with water

28 Tablets

Rx Only

Pharmacyclics LLC
An AbbVie Company

Janssen Biotech, Inc.

 

PRINCIPAL DISPLAY PANEL - 28 Tablet Blister Strip (Front)

NDC 57962-420-28

Imbruvica®
(ibrutinib) tablets

420 mg

Each table contains: ibrutinib 420 mg
Swallow tablet whole with water

28 Tablets

Rx Only

Pharmacyclics LLC
An AbbVie Company

Janssen Biotech, Inc.

 

PRINCIPAL DISPLAY PANEL - 28 Tablet Blister Strip (Back)

NDC 57962-420-28

Imbruvica®
(ibrutinib) tablets

420 mg

Each table contains: ibrutinib 420 mg
Swallow tablet whole with water

28 Tablets

Rx Only

Pharmacyclics LLC
An AbbVie Company

Janssen Biotech, Inc.

 

PRINCIPAL DISPLAY PANEL - 28 Tablet Blister Carton

NDC 57962-560-28

Imbruvica®
(ibrutinib) tablets

560 mg

Each table contains: ibrutinib 560 mg
Swallow tablet whole with water

28 Tablets

Rx Only

Pharmacyclics LLC
An AbbVie Company

Janssen Biotech, Inc.

 

PRINCIPAL DISPLAY PANEL - 28 Tablet Blister Strip (Front)

NDC 57962-560-28

Imbruvica®
(ibrutinib) tablets

560 mg

Each table contains: ibrutinib 560 mg
Swallow tablet whole with water

28 Tablets

Rx Only

Pharmacyclics LLC
An AbbVie Company

Janssen Biotech, Inc.

 

PRINCIPAL DISPLAY PANEL - 28 Tablet Blister Strip (Back)

NDC 57962-560-28

Imbruvica®
(ibrutinib) tablets

560 mg

Each table contains: ibrutinib 560 mg
Swallow tablet whole with water

28 Tablets

Rx Only

Pharmacyclics LLC
An AbbVie Company

Janssen Biotech, Inc.

 

Imbruvica ibrutinib capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:57962-070 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength IBRUTINIB (IBRUTINIB) IBRUTINIB 70 mg

Product Characteristics Color YELLOW Score no score Shape CAPSULE Size 18mm Flavor   Imprint Code ibr;70;mg Contains

Packaging # Item Code Package Description   1 NDC:57962-070-28 28 CAPSULE in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA205552 12/20/2017

Imbruvica ibrutinib capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:57962-140 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength IBRUTINIB (IBRUTINIB) IBRUTINIB 140 mg

Product Characteristics Color WHITE Score no score Shape CAPSULE Size 22mm Flavor   Imprint Code ibr;140;mg Contains

Packaging # Item Code Package Description   1 NDC:57962-140-09 90 CAPSULE in 1 BOTTLE, PLASTIC   2 NDC:57962-140-12 120 CAPSULE in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA205552 11/13/2013

Imbruvica ibrutinib tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:57962-014 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength IBRUTINIB (IBRUTINIB) IBRUTINIB 140 mg

Product Characteristics Color GREEN (Yellow-green to green) Score no score Shape ROUND Size 9mm Flavor   Imprint Code ibr;140 Contains

Packaging # Item Code Package Description   1 NDC:57962-014-28 1 BLISTER PACK in 1 CARTON   1   28 TABLET, FILM COATED in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA210563 02/16/2018

Imbruvica ibrutinib tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:57962-280 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength IBRUTINIB (IBRUTINIB) IBRUTINIB 280 mg

Product Characteristics Color PURPLE Score no score Shape OVAL (Oblong) Size 15mm Flavor   Imprint Code ibr;280 Contains

Packaging # Item Code Package Description   1 NDC:57962-280-28 1 BLISTER PACK in 1 CARTON   1   28 TABLET, FILM COATED in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA210563 02/16/2018

Imbruvica ibrutinib tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:57962-420 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength IBRUTINIB (IBRUTINIB) IBRUTINIB 420 mg

Product Characteristics Color GREEN (Yellow-green to green) Score no score Shape OVAL (Oblong) Size 18mm Flavor   Imprint Code ibr;420 Contains

Packaging # Item Code Package Description   1 NDC:57962-420-28 1 BLISTER PACK in 1 CARTON   1   28 TABLET, FILM COATED in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA210563 02/16/2018

Imbruvica ibrutinib tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:57962-560 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength IBRUTINIB (IBRUTINIB) IBRUTINIB 560 mg

Product Characteristics Color YELLOW (Yellow to orange) Score no score Shape OVAL (Oblong) Size 19mm Flavor   Imprint Code ibr;560 Contains

Packaging # Item Code Package Description   1 NDC:57962-560-28 1 BLISTER PACK in 1 CARTON   1   28 TABLET, FILM COATED in 1 BLISTER PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA210563 02/16/2018

Labeler - Pharmacyclics LLC (079857498)
Establishment
Name	Address	ID/FEI	Operations
Pharmacyclics LLC		079857498	ANALYSIS(57962-140, 57962-070, 57962-014, 57962-280, 57962-420, 57962-560)

 

Pharmacyclics LLC