6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling.

Hepatotoxicity [see Warnings and Precautions (5.1)]
Severe Diarrhea or Colitis [see Warnings and Precautions (5.2)]
Pneumonitis [see Warnings and Precautions (5.3)]
Infections [see Warnings and Precautions (5.4)]
Intestinal Perforation [see Warnings and Precautions (5.5)]
Severe Cutaneous Reactions [see Warnings and Precautions (5.6)]
Hypersensitivity Reactions [see Warnings and Precautions (5.7)]
Neutropenia [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to Zydelig at a dosage of 150 mg twice daily in 110 patients administered in combination with rituximab in Study 312-0116, and in combination with other drugs in 380 patients. Among 490 patients who received Zydelig, 74% were exposed for 6 months or longer and 50% were exposed for one year or longer. In this pooled safety population, the most common (> 30%) adverse reactions were diarrhea, pneumonia, pyrexia, fatigue, rash, cough, and nausea. Common laboratory abnormalities were neutropenia, ALT elevations and AST elevations.

Summary of Clinical Trials in Chronic Lymphocytic Leukemia

The safety data reflect exposure to Zydelig from two randomized, double-blind clinical trials (Studies 312-0116 and 312-0115) in 634 patients with relapsed CLL [see Clinical Studies (14.1)] and one randomized, open-label trial in 259 patients with relapsed CLL (Study 312-0119).

Zydelig with Rituximab (Study 312-0116)

Patients with relapsed CLL received up to 8 doses of rituximab (R) with (n=110) or without Zydelig (n=108)150 mg twice daily. The median duration of exposure to Zydelig was 8 months.

Serious adverse reactions were reported in 65 (59%) patients treated with Zydelig + R The most frequent serious adverse reactions reported for patients treated with Zydelig + R were pneumonia (23%), diarrhea (10%), pyrexia (9%), sepsis (8%), and febrile neutropenia (5%).

Adverse reactions that led to discontinuation of Zydelig occurred in 19 (17%) patients. The most common adverse reactions that led to treatment discontinuations were hepatotoxicity and diarrhea/colitis.

Forty-two (38%) patients had dose interruptions and sixteen (15%) patients had dose reductions due to adverse reactions or laboratory abnormalities. The most common reasons for dose interruptions or reductions were pneumonia, diarrhea or colitis, rash, and elevated transaminases.

Table 2 and Table 3 summarize common adverse reactions and laboratory abnormalities reported for Zydelig + R and placebo + R arms.

Table 2 Adverse Reactions Reported in ≥5% of Patients with CLL and Occurred at ≥2% Higher Incidence in Patients Receiving Zydelig in Study 312-0116
	Zydelig + R N=110 (%)		Placebo + R N=108 (%)
Adverse Reaction	Any Grade	Grade ≥3	Any Grade	Grade ≥3
* Diarrhea includes the following preferred terms: diarrhea, colitis. † Abdominal pain includes the following preferred terms: abdominal pain, abdominal pain upper, abdominal pain lower. ‡ Pneumonia includes the terms: pneumonia, pneumonitis, lung infection, lung infiltration, pneumocystis jiroveci pneumonia, pneumonia legionella, lung infection pseudomonal, pneumonia fungal, respiratory tract infection, lower respiratory tract infection, and lower respiratory tract infection bacterial. § Rash includes the following preferred terms: dermatitis exfoliative, drug eruption, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash morbilliform, and exfoliative rash. ¶ Sepsis includes the terms: sepsis, septic shock, neutropenic sepsis, and sepsis syndrome
General disorders and administration site conditions
pyrexia	44 (40)	3 (3)	20 (19)	1 (1)
chills	27 (25)	2 (2)	17 (16)	0
pain	8 (7)	0	1 (1)	0
Gastrointestinal disorders
diarrhea *	35 (32)	12 (11)	20 (19)	0
nausea	30 (27)	1 (1)	25 (23)	0
abdominal pain †	20 (18)	1 (1)	17 (16)	2 (2)
vomiting	17 (15)	0	9 (8)	0
gastroesophageal reflux disease	11 (10)	1 (1)	0	0
stomatitis	7 (6)	2 (2)	1 (1)	0
Respiratory, thoracic, and mediastinal disorders
pneumonia ‡	33 (30)	23 (21)	20 (19)	14 (13)
Skin and subcutaneous tissue disorders
rash §	27 (25)	4 (4)	7 (6)	1 (1)
Metabolism and Nutrition Disorders
decreased appetite	18 (16)	2 (2)	12 (11)	2 (2)
dehydration	7 (6)	3 (3)	0	0
Infections and infestations
sepsis ¶	10 (9)	10 (9)	4 (4)	4 (4)
sinusitis	9 (8)	0	6 (6)	0
urinary tract infection	9 (8)	1 (1)	4 (4)	2 (2)
bronchitis	8 (7)	1 (1)	5 (5)	1 (1)
oral herpes	6 (5)	1 (1)	3 (3)	0
Psychiatric disorders
insomnia	10 (9)	0	7 (6)	0
Musculoskeletal and connective tissue disorders
arthralgia	9 (8)	1 (1)	4 (4)	0
Nervous system disorders
lethargy	6 (5)	0	2 (2)	0

Table 3 Hematologic and Hepatic Laboratory Abnormalities Reported in ≥10% of Patients with CLL and Occurred at ≥5% Higher Incidence in Patients Receiving Zydelig in Study 312-0116
	Zydelig + R N=110 (%)		Placebo + R N=108 (%)
Laboratory Parameter	Any Grade	Grade 3–4	Any Grade	Grade 3–4
Hematology abnormalities
neutropenia	71 (65)	46 (42)	61 (56)	33 (31)
leukopenia	34 (31)	9 (8)	25 (23)	9 (8)
lymphocytopenia	23 (21)	11 (10)	13 (12)	4 (4)
Serum chemistry abnormalities
ALT increased	43 (39)	10 (9)	13 (12)	1 (1)
AST increased	31 (28)	6 (5)	16 (15)	0

After closure of Study 312-0116, 71 patients continued treatment with Zydelig on an extension study (Study 312-0117). The median duration of exposure was 18 months. Serious adverse reactions occurred in 48 (68%) patients. The most frequent serious adverse reactions reported were pneumonia (30%), diarrhea (15%), and pyrexia (11%).

The most frequent adverse reactions were pneumonia (51%), pyrexia (46%), and cough (45%). The most frequent Grade 3 or greater adverse reactions were pneumonia (30%), diarrhea (15%), and sepsis (10%).

Zydelig with Ofatumumab (Study 312-0119)

In Study 312-0119, 259 patients with relapsed CLL received up to 12 doses of ofatumumab with or without Zydelig 150 mg orally twice daily. Zydelig in combination with ofatumumab is not indicated for the treatment of relapsed CLL. The median duration of exposure to Zydelig was 13.9 months.

Serious adverse reactions were reported in 133 (77%) patients treated with Zydelig + ofatumumab. The most frequent serious adverse reactions reported were pneumonia (14%), pyrexia (13%), and diarrhea (12%).

Adverse reactions that led to discontinuation of Zydelig occurred in 71 (41%) patients.

One hundred and ten (64%) patients had dose interruptions and 42 (24%) patients had dose reductions due to adverse reactions or laboratory abnormalities. The most common reasons for dose discontinuations, reductions, or interruptions were diarrhea and colitis.

The most common adverse reactions were diarrhea (55%), pyrexia (38%), nausea (34%), and fatigue (34%).

Zydelig with Bendamustine and Rituximab (Study 312-0115)

In Study 312-0115, patients with relapsed CLL received up to 6 cycles of bendamustine and rituximab (BR) with or without Zydelig 150 mg orally twice daily. Zydelig in combination with bendamustine and rituximab is not indicated for the treatment of relapsed CLL. The median duration of exposure to Zydelig was 18.2 months.

Serious adverse reactions were reported in 147 (71%) patients treated with Zydelig + BR. The most frequent serious adverse reactions reported for patients treated with Zydelig + BR were febrile neutropenia (21%), pneumonia (17%), pyrexia (12%), and diarrhea (6%).

Adverse reactions that led to discontinuation of Zydelig occurred in 68 (33%) patients. The most common adverse reactions that led to treatment discontinuations were pneumonia, diarrhea, and pyrexia.

One hundred twenty-two (59%) patients treated with Zydelig + BR had dose interruptions and 34 (16%) patients had dose reductions due to adverse reactions. The most common reasons for dose interruptions or reductions were increased ALT and diarrhea.

The most common adverse reactions were neutropenia (64%), pyrexia (43%), and diarrhea (41%).

Summary of Clinical Trials in Indolent Non-Hodgkin Lymphoma

The safety data reflect exposure to Zydelig from three open-label clinical trials (Studies 101-09, 101-02, and 101-10 in 146 patients with indolent non-Hodgkin lymphoma (iNHL) treated with Zydelig 150 mg orally twice daily. Zydelig is not indicated for the treatment of iNHL. The median duration of exposure was 6.1 months (range 0.3 to 26.4 months).

Serious adverse reactions were reported in 73 (50%) patients. The most frequent serious adverse reactions that occurred were pneumonia (15%), diarrhea (11%), and pyrexia (9%).

Adverse reactions resulted in interruption or discontinuation for 78 (53%) patients. The most common reasons for interruption or discontinuations were diarrhea (11%), pneumonia (11%), and elevated transaminases (10%).

The most common adverse reactions were neutropenia (53%), ALT increased (50%), diarrhea (47%), AST increased (41%), fatigue (30%), nausea and cough (29% each), anemia and pyrexia (28% each), abdominal pain and thrombocytopenia (26% each), and pneumonia (25%).

Summary of Discontinued Clinical Trials in Indolent Non-Hodgkin Lymphoma and First-Line CLL

Zydelig is not indicated for patients with indolent non-Hodgkin lymphoma or previously untreated CLL either as monotherapy or in combination with rituximab or BR. Safety data described below reflect exposure to Zydelig in three randomized, double-blind clinical trials (Studies 312-0123, 313-0124, and 313-0125) in patients with CLL and iNHL.

In Study 312-0123 (NCT01980888), 311 patients with previously untreated CLL received up to 6 cycles of BR with or without Zydelig 150 mg twice daily.

In Study 313-0124 (NCT01732913), 295 patients with previously treated iNHL [FL 66%, marginal zone lymphoma (MZL) 19%, SLL 9%, lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM) 6%] received 8 doses of R with or without Zydelig 150 mg twice daily. Patients had a median of one prior therapy.

In Study 313-0125 (NCT01732926), 475 patients with previously treated iNHL (FL 63%, MZL 15%, SLL 11%, LPL/WM 11%) received up to 6 cycles of BR with or without Zydelig 150 mg twice daily. Patients had a median of two prior therapies.

These three studies were terminated early due to a higher incidence of fatal and/or serious adverse reactions observed in patients treated with Zydelig in combination with R or BR. The most frequent serious adverse reactions were in the system organ classes of infections and infestations, blood and lymphatic system disorders, and gastrointestinal disorders.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Zydelig. 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.

Skin and Subcutaneous Disorders - Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)