ZYDELIG SIDE EFFECTS
- Generic Name: idelalisib tablets
- Brand Name: Zydelig
- Drug Class: , Antineoplastics PI3K Inhibitors
SIDE EFFECTS
The following clinically significant adverse reactions are described elsewhere in the labeling.
- Hepatotoxicity
- Severe Diarrhea or Colitis
- Pneumonitis
- Infections
- Intestinal Perforation
- Severe Cutaneous Reactions
- Hypersensitivity Reactions
- Neutropenia
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.
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)
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 1 and Table 2 summarize common adverse reactions and laboratory abnormalities reported for Zydelig + R and placebo + R arms.
Table 1: 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 GGrade ≥3rade | 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 |
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Table 2: 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). 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. 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. 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.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 3provides the adverse reactions occurring in at least 10% of patients receiving Zydelig monotherapy and Table 4 provides the hematologic and hepatic laboratory abnormalities.
Table 3: Adverse Reactions Reported in ≥ 10% of Patients with Indolent NHL Treated with Zydelig
| 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. |
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Table 4: Hematologic and Hepatic Laboratory Abnormalities in Patients with Indolent non-Hodgkin Lymphoma Treated with Zydelig
| Zydelig Monotherapy N=146 (%) |
|||
| Laboratory Abnormality | 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 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).
SRC: NLM .