ASH Clinical News December 2016 | Page 12

Brief Summary of Prescribing Information for IMBRUVICA ® ( ibrutinib ) IMBRUVICA ® ( ibrutinib ) capsules , for oral use See package insert for Full Prescribing Information

INDICATIONS AND USAGE Mantle Cell Lymphoma : IMBRUVICA is indicated for the treatment of 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 of clinical benefit in confirmatory trials [ see Clinical Studies ( 14.1 ) in Full Prescribing Information ].

Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma : IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia ( CLL )/ small lymphocytic lymphoma ( SLL ) [ see Clinical Studies ( 14.2 ) in Full Prescribing Information ]. Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma with 17p deletion : IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia ( CLL )/ small lymphocytic lymphoma ( SLL ) with 17p deletion [ see Clinical Studies ( 14.2 ) in Full Prescribing Information ]. Waldenström ’ s Macroglobulinemia : IMBRUVICA is indicated for the treatment of patients with Waldenström ’ s macroglobulinemia ( WM ) [ see Clinical Studies ( 14.3 ) in Full Prescribing Information ].

CONTRAINDICATIONS None

WARNINGS AND PRECAUTIONS Hemorrhage : 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 up to 6 % of patients . Bleeding events of any grade , including bruising and petechiae , occurred in approximately half 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 ) in Full Prescribing Information ].

Infections : Fatal and non-fatal infections have occurred with IMBRUVICA therapy . Grade 3 or greater infections occurred in 14 % to 29 % of patients [ see Adverse Reactions ]. Cases of progressive multifocal leukoencephalopathy ( PML ) have occurred in patients treated with IMBRUVICA . Evaluate patients for fever and infections and treat appropriately .

Cytopenias : Treatment-emergent Grade 3 or 4 cytopenias including neutropenia ( range , 19 to 29 %), thrombocytopenia ( range , 5 to 17 %), and anemia ( range , 0 to 9 %) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA .

Monitor complete blood counts monthly .

Atrial Fibrillation : Atrial fibrillation and atrial flutter ( range , 6 to 9 %) have occurred in patients treated with IMBRUVICA , particularly in patients with cardiac risk factors , hypertension , acute infections , and a previous history of atrial fibrillation . Periodically monitor patients clinically for atrial fibrillation . Patients who develop arrhythmic symptoms ( e . g ., palpitations , lightheadedness ) or new onset dyspnea should have an ECG performed . Atrial fibrillation should be managed appropriately , and if it persists , consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines [ see Dosage and Administration ( 2.3 ) in Full Prescribing Information ].

Hypertension : Hypertension ( range , 6 to 17 %) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 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 ( range , 5 to 16 %) including non-skin carcinomas ( range , 1 to 4 %) have occurred in patients treated with IMBRUVICA . The most frequent second primary malignancy was non-melanoma skin cancer ( range , 4 to 13 %).

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 embryofetal toxicity including malformations at exposures that were 2-20 times higher than those reported in patients with MCL , CLL / SLL or WM . 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 ].

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

• Hemorrhage [ see Warnings and Precautions ]

• Infections [ see Warnings and Precautions ]

• Cytopenias [ see Warnings and Precautions ]

• Atrial Fibrillation [ see Warnings and Precautions ]

• Hypertension [ see Warnings and Precautions ]

• Second Primary Malignancies [ see Warnings and Precautions ]

• Tumor Lysis Syndrome [ see Warnings and Precautions ]

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 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 thrombo cytopenia , 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 .

Infections and infestations

Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis

34 14 14 14 13

0 3 7 5 1

IMBRUVICA ® ( ibrutinib ) capsules

Table 1 : Non-Hematologic Adverse Reactions in ≥ 10 % of Patients with MCL ( N = 111 ) ( continued )

Grade 3 or 4 All Grades (%)

Body System Adverse Reaction

(%)

General disorders and administration site conditions

Skin and subcutaneous tissue disorders

Musculoskeletal and connective tissue disorders

Respiratory , thoracic and mediastinal disorders

Metabolism and nutrition disorders

Nervous system disorders

Fatigue Peripheral edema Pyrexia Asthenia

Bruising Rash Petechiae

Musculoskeletal pain Muscle spasms Arthralgia

Dyspnea Cough Epistaxis

Decreased appetite Dehydration

Dizziness Headache

41 35 18 14

30 25 11

37 14 11

27 19 11

21 12

14 13

Table 2 : Treatment-Emergent * Decrease of Hemoglobin , Platelets , or Neutrophils in Patients with MCL ( N = 111 )

Percent of Patients ( N = 111 )

All Grades (%)

Grade 3 or 4 (%)

Platelets Decreased 57 17 Neutrophils Decreased 47 29 Hemoglobin Decreased 41 9 * Based on laboratory measurements and adverse reactions

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 and three randomized controlled clinical trials in patients with CLL / SLL ( n = 1278 total and n = 668 patients exposed to IMBRUVICA ). Study 1 included 51 patients with previously treated CLL / SLL , Study 2 included 391 randomized patients with previously treated CLL or SLL who received single agent IMBRUVICA or ofatumumab , Study 3 included 269 randomized patients 65 years or older with treatment naïve-CLL or SLL who received single agent IMBRUVICA or chlorambucil and Study 4 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 1 , 2 , 3 and 4 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 1 , 2 , 3 and 4 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 1 : 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 1

Grade 3 or 4 All Grades (%)

Body System Adverse Reaction

(%)

Gastrointestinal disorders

Infections and infestations

General disorders and administration site conditions

Skin and subcutaneous tissue disorders

Respiratory , thoracic and mediastinal disorders

Musculoskeletal and connective tissue disorders

Nervous system disorders

Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia

Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection

Fatigue Pyrexia Peripheral edema Asthenia Chills

Bruising Rash Petechiae

Cough Oropharyngeal pain Dyspnea

Musculoskeletal pain Arthralgia Muscle spasms

Dizziness Headache

59 22 20 20 18 14 12

47 22 16 12 12

33 24 22 14 12

51 25 16

22 14 12

25 24 18

20 18

5 3 1 3

0 3 0

1 0 0

4 0 0

2 4

0 0

4 2 2 0 2 0 0

2 6 6 10 2

6 2 0 6 0

2 0 0

0 0 0

6 0 2

0 2