Cancer Medication Side Effects & Warnings


What are the side effects of Zydelig?

The following serious adverse reactions have been
associated with Zydelig in clinical trials and are discussed in greater detail
in other sections of the prescribing information.

  • Hepatotoxicity
  • Severe Diarrhea or Colitis
  • Pneumonitis
  • Infections
  • Intestinal Perforation
  • Severe Cutaneous Reactions
  • Anaphylaxis
  • Neutropenia

Clinical Trial 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.

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 and one randomized,
open-label trial in 259 patients with relapsed CLL (Study 312-0119).

Zydelig With Rituximab (Study 312-0116; NCT01539512)

Patients with relapsed CLL received up to 8 doses of
rituximab (R) with or without Zydelig 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

Adverse Reaction Zydelig + R
N=110 (%)
Placebo + R
N=108(%)
Any Grade Grade ≥3 Any Grade Grade ≥3
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 (a) 35 (32) 12 (11) 20 (19) 0
nausea 30 (27) 1 (1) 25 (23) 0
abdominal pain (b) 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 (c) 33 (30) 23 (21) 20 (19) 14 (13)
Skin and subcutaneous tissue disorders
rash (d) 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 (e) 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
(a) Diarrhea includes the following preferred terms: diarrhea,
colitis.
(b) Abdominal pain includes the following preferred terms: abdominal pain,
abdominal pain upper, abdominal pain lower.
(c) 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.
(d) 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.
(e) Sepsis includes the terms: sepsis, septic shock, neutropenic sepsis, and
sepsis syndrome

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

Laboratory Parameter Zydelig + R
N=110(%)
Placebo + R
N=108 (%)
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; NCT01539291). 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; NCT01659021)

In Study 312-0119, 259 patients with relapsed CLL
received up to 12 doses of ofatumumab with or without Zydelig 150 mg twice
daily. 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

Zydelig With Bendamustine And Rituximab (Study 312-0115;
NCT01569295)

In Study 312-0115, patients with relapsed CLL received up
to 6 cycles of bendamustine and rituximab (BR) with or without Zydelig 150 mg
twice daily. 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 (NCT01282424), 101-02 (NCT00710528), and 101-10
(NCT01306643) in 146 patients with indolent non-Hodgkin lymphoma (iNHL) treated
with Zydelig 150 mg twice daily.
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%).

Table 4 provides the adverse reactions occurring in at
least 10% of patients receiving Zydelig monotherapy, and Table 5 provides the
hematologic and hepatic laboratory abnormalities.

Table 4 : Adverse Reactions Reported in ≥ 10% of
Patients with Indolent NHL Treated with Zydelig 150 mg BID

Adverse Reaction Zydelig Monotherapy
N=146(%)
Any Grade Grade ≥3
Gastrointestinal disorders
diarrhea (a) 68 (47) 20 (14)
nausea 42 (29) 2 (1)
abdominal pain (b) 38 (26) 3 (2)
vomiting 22 (15) 2 (1)
General disorders and administration site conditions
fatigue 44 (30) 2 (1)
pyrexia 41 (28) 3 (2)
asthenia 17 (12) 3 (2)
peripheral edema 15 (10) 3 (2)
Respiratory, thoracic, and mediastinal disorders
cough 42 (29) 1 (1)
pneumonia (c) 37 (25) 23 (16)
dyspnea 25 (17) 6 (4)
Skin and subcutaneous disorders
rash (d) 31 (21) 4 (3)
night sweats 18 (12) 0
Metabolism and nutrition disorders
decreased appetite 24 (16) 1 (1)
Infections and infestations
upper respiratory tract infection 18 (12) 0
Psychiatric disorders
insomnia 17 (12) 0
Nervous system disorders
headache 16 (11) 1 (1)
(a) Diarrhea includes the following preferred terms:
diarrhea, colitis, enterocolitis, and gastrointestinal inflammation.
(b) Abdominal pain includes the following preferred terms: abdominal pain,
abdominal pain upper, abdominal pain lower, and abdominal discomfort.
(c) Pneumonia includes the terms: pneumonia, pneumonitis, interstitial lung
disease, lung infiltration, pneumonia aspiration, respiratory tract infection,
atypical pneumonia, lung infection, pneumocystis jiroveci pneumonia, bronchopneumonia,
pneumonia necrotizing, lower respiratory tract infection, pneumonia
pneumococcal, pneumonia staphylococcal, pneumonia streptococcal, pneumonia
cytomegaloviral, and respiratory syncytial virus infection.
(d) Rash includes the following preferred terms: dermatitis exfoliative, rash,
rash erythematous, rash macular, rash maculo-papular, rash pruritic, and
exfoliative rash.

Table 5 : Hematologic and Hepatic Laboratory
Abnormalities in Patients with Indolent non-Hodgkin Lymphoma Treated with
Zydelig 150 mg BID

Laboratory Abnormality Zydelig Monotherapy
N=146(%)
Any Grade Grade 3 Grade 4
Serum chemistry abnormalities
ALT increased 73 (50) 20 (14) 7 (5)
AST increased 60 (41) 12 (8) 6 (4)
Hematology abnormalities
neutrophils decreased 78 (53) 20 (14) 16 (11)
hemoglobin decreased 41 (28) 3 (2) 0
platelets decreased 38 (26) 4 (3) 5 (3)
Grades were obtained per CTCAE version 4.03.

Summary Of Discontinued Clinical Trials In First-Line CLL
and Early Line iNHL
  • Safety data described below reflect exposure to Zydelig
    in three randomized, doubleblind 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 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 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.

Postmarketing Experience

The following adverse reactions have been identified
during post-approval use of Zydelig. Because postmarketing 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)





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