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IMBRUVICA ® ( ibrutinib ) capsules

Table 12 : Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with MZL in Study 1121 ( N = 63 )

Percent of Patients ( N = 63 )

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 13 and 14 reflect exposure to IMBRUVICA with a median duration of 4.4 months in the cGVHD trial .

Table 13 : Non-Hematologic Adverse Reactions in ≥ 10 % of Patients with cGVHD ( N = 42 )

Body System

General disorders and administration site conditions

Skin and subcutaneous tissue disorders

Gastrointestinal disorders

Musculoskeletal and connective tissue disorders

Adverse Reaction

Fatigue Pyrexia Edema peripheral

Bruising * Rash *

Diarrhea Stomatitis * Nausea Constipation

Muscle spasms Muscoloskeletal pain *

All Grades (%)

57 17 12

40 12

36 29 26 12

29

Grade 3 or 4 (%)

12 5 0

0 0

10 2 0 0

2

Nervous system disorders

Injury , poisoning and procedural complications

Respiratory , thoracic and mediastinal disorders

Metabolism and nutrition disorders

Pneumonia * Upper respiratory tract infection Sepsis *

Fall 17 0

Cough Dyspnea

14 12

Hypokalemia 12 7

Additional Important Adverse Reactions : Cardiac Arrhythmias : In randomized controlled trials ( n = 1227 ; median treatment duration of 13.1 months for patients treated with IMBRUVICA and 9.0 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 0.2 % and of Grade 3

0 2

IMBRUVICA ® ( ibrutinib ) capsules

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 7 % versus 1.5 % and for Grade 3 or greater was 2.8 % versus 0.3 % in patients treated with IMBRUVICA compared to patients in the control arm .

Diarrhea : Diarrhea of any grade occurred at a rate of 43 % ( range , 36 % to 59 %) of patients treated with IMBRUVICA . Grade 2 diarrhea occurred in 9 % ( range , 3 % to 14 %) and Grade 3 in 3 % ( range , 0 to 5 %) of patients treated with IMBRUVICA . The median time to first onset of any grade diarrhea was 10 days ( range , 0 to 627 ), of Grade 2 was 39 days ( range , 1 to 719 ) and of Grade 3 was 74 days ( range , 3 to 627 ). Of the patients who reported diarrhea , 82 % had complete resolution , 1 % had partial improvement and 17 % had no reported improvement at time of analysis . The median time from onset to resolution or improvement of any grade diarrhea was 5 days ( range , 1 to 418 ), and was similar for Grades 2 and 3 . Less than 1 % of patients discontinued IMBRUVICA due to diarrhea .

Visual Disturbance : Blurred vision and decreased visual acuity of any grade occurred in 10 % of patients treated with IMBRUVICA ( 9 % Grade 1 , 2 % Grade 2 ). The median time to first onset was 85 days ( range , 1 to 414 days ). Of the patients with visual disturbance , 61 % had complete resolution and 38 % had no reported improvement at time of analysis . The median time from onset to resolution or improvement was 29 days ( range , 1 to 335 days ).

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

• Respiratory disorders : interstitial lung disease

• Metabolic and nutrition disorders : tumor lysis syndrome [ see Warnings & Precautions ]

• Immune system disorders : anaphylactic shock , angioedema , urticaria

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

• Infections : hepatitis B reactivation

DRUG INTERACTIONS Effect of CYP3A Inhibitors on Ibrutinib : The coadministration of IMBRUVICA with a strong or moderate CYP3A inhibitor may increase ibrutinib plasma concentrations [ see Clinical Pharmacology ( 12.3 ) in Full Prescribing Information ]. 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 ) in Full Prescribing Information ].

Avoid concomitant use of other strong CYP3A inhibitors . Interrupt IMBRUVICA if these inhibitors will be used short-term ( such as antiinfectives for seven days or less ) [ see Dosage and Administration in Full Prescribing Information ].

Examples a of strong CYP3A inhibitors include : boceprevir , clarithromycin , cobicistat conivaptan , danoprevir and ritonavir , diltiazem , elvitegravir and ritonavir , idelalisib , indinavir and ritonavir , itraconazole , ketoconazole , lopinavir and ritonavir , nefazodone , nelfinavir , paritaprevir and ritonavir and ( ombitasvir and / or dasabuvir ), ritonavir , saquinavir and ritonavir , tipranavir and ritonavir , and troleandomycin .

Examples a of moderate CYP3A inhibitors include : aprepitant , cimetidine , ciprofloxacin , clotrimazole , crizotinib , cyclosporine , dronedarone , erythromycin , fluconazole , fluvoxamine , imatinib , tofisopam , and verapamil .

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 ) in Full Prescribing Information ].

Examples a of strong CYP3A inducers include : carbamazepine , enzalutamide , mitotane , phenytoin , rifampin , and St . John ’ s wort b .

a These examples are a guide and not considered a comprehensive list of all

possible drugs that may fit this category . The healthcare provider should consult appropriate references for comprehensive information . b

The induction potency of St . John ’ s wort may vary widely based on preparation .

USE IN SPECIFIC POPULATIONS Pregnancy : 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 ,