ASH Clinical News Focus on Myeloid Malignancies | Page 31

IMBRUVICA ® ( ibrutinib ) capsules

Skin and subcutaneous tissue disorders

General disorders and administrative site conditions Musculoskeletal and connective tissue disorders Infections and infestations

Respiratory , thoracic and mediastinal disorders Nervous system disorders

Neoplasms benign , malignant , and unspecified ( including cysts and polyps )

Rash * Bruising * Pruritus

22 16 11

0 0 0 Fatigue 21 0

Muscle spasms Arthropathy

Upper respiratory tract infection Sinusitis Pneumonia * Skin infection *

21 13

19 19 14 14 19 13 14 13

0 0

0 0 6 2 0 0 0 0

The body system and individual ADR preferred terms are sorted in descending frequency order . * Includes multiple ADR terms .

General disorders and administrative site conditions

Skin and subcutaneous tissue disorders

Musculoskeletal and connective tissue disorders

Infections and infestations

Diarrhea Nausea Dyspepsia Stomatitis * Abdominal pain Constipation Abdominal pain Upper Vomiting

Fatigue Peripheral edema Pyrexia

Bruising * Rash * Pruritus

Musculoskeletal pain * Arthralgia Muscle spasms

Upper respiratory tract infection Sinusitis * Bronchitis Pneumonia *

43 25 19 17 16 14 13 11

44 24 17

41 29 14

40 24 19

21 19 11 11

5 0 0 2 2 0 0 2

6 2 2

0 5 0

3 2 3

0 0 0 10

IMBRUVICA ® ( ibrutinib ) capsules

Decreased appetite Hyperuricemia Hypoalbuminemia Hypokalemia

16 16 14 13

30 14

22 21

Table 12 : Treatment-Emergent * Decrease of Hemoglobin , Platelets , or Neutrophils in Patients with MZL in Study 6 ( 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 * Based on laboratory measurements .

Additional Important Adverse Reactions : 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

DRUG INTERACTIONS CYP3A Inhibitors : Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A ( CYP3A ). In healthy volunteers , co-administration of ketoconazole , a strong CYP3A inhibitor , increased C max and AUC of ibrutinib by 29- and 24-fold , respectively . The highest ibrutinib dose evaluated in clinical trials was 12.5 mg / kg ( actual doses of 840 – 1400 mg ) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr / mL which is approximately 50 % greater than steady state exposures seen at the highest indicated dose ( 560 mg ).

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

2 0 0 0

0 5

2 2