1.1 Mantle Cell Lymphoma

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

1.2 Chronic Lymphocytic Leukemia

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

2.1 Dosing Guidelines

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

2.2 Dosage

2.3 Dose Modifications for Adverse Reactions

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

Recommended dose modifications for these toxicities are described below:

2.4 Dose Modifications for Use with CYP3A Inhibitors

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

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

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

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

2.5 Missed Dose

If a dose of IMBRUVICA is not taken at the scheduled time, it can be taken as soon as possible on the same day with a return to the normal schedule the following day. Extra capsules of IMBRUVICA should not be taken to make up for the missed dose.

5.1 Hemorrhage

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

The mechanism for the bleeding events is not well understood.

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

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14)].

5.2 Infections

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

5.3 Myelosuppression

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

Monitor complete blood counts monthly.

5.4 Renal Toxicity

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

5.5 Second Primary Malignancies

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

5.6 Embryo-Fetal Toxicity

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