Zydelig Drug Information

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 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 General disorders and administration site conditions pyrexia 44 3 20 1 chills 27 2 17 0 pain 8 0 1 0 Gastrointestinal disorders diarrhea Diarrhea includes the following preferred terms: diarrhea, colitis. 35 12 20 0 nausea 30 1 25 0 abdominal pain Abdominal pain includes the following preferred terms: abdominal pain, abdominal pain upper, abdominal pain lower. 20 1 17 2 vomiting 17 0 9 0 gastroesophageal reflux disease 11 1 0 0 stomatitis 7 2 1 0 Respiratory, thoracic, and mediastinal disorders pneumonia 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. 33 23 20 14 Skin and subcutaneous tissue disorders rash 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. 27 4 7 1 Metabolism and Nutrition Disorders decreased appetite 18 2 12 2 dehydration 7 3 0 0 Infections and infestations sepsis Sepsis includes the terms: sepsis, septic shock, neutropenic sepsis, and sepsis syndrome 10 10 4 4 sinusitis 9 0 6 0 urinary tract infection 9 1 4 2 bronchitis 8 1 5 1 oral herpes 6 1 3 0 Psychiatric disorders insomnia 10 0 7 0 Musculoskeletal and connective tissue disorders arthralgia 9 1 4 0 Nervous system disorders lethargy 6 0 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 46 61 33 leukopenia 34 9 25 9 lymphocytopenia 23 11 13 4 Serum chemistry abnormalities ALT increased 43 10 13 1 AST increased 31 6 16 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 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.

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)

Effects of Other Drugs on Zydelig Table 6 lists the potential effects

of the coadministration of strong CYP3A modulators on Zydelig. Table 6 Drug Interactions with Zydelig that affect Idelalisib Concentrations Strong CYP3A Inhibitors Clinical Impact Coadministration with strong CYP3A inhibitors may increase idelalisib concentrations . Increased idelalisib concentrations may increase the risk of exposure related adverse reactions. Prevention or Management Use other drugs that are not strong CYP3A inhibitors.

If unable to use alternative drugs, monitor patients more frequently for Zydelig adverse reactions . Strong CYP3A Inducers Clinical Impact Coadministration with strong CYP3A inducers may decrease idelalisib concentrations . Decreased idelalisib concentrations may reduce efficacy. Prevention or Management Avoid coadministration of Zydelig with strong CYP3A4 inducers.

Effects of Zydelig on Other Drugs

The coadministration of Zydelig with a CYP3A substrate may increase the concentrations of this CYP3A substrate. Avoid coadministration of Zydelig with sensitive CYP3A substrates.

Pregnancy Risk Summary Based on findings in animal studies and the mechanism of action , Zydelig may cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of idelalisib to pregnant rats during organogenesis resulted in decreased fetal weight and congenital malformations in rats at maternal exposures (AUC) 12 times those reported in patients at the recommended dosage of 150 mg twice daily (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies 2–4% and 15–20%, respectively. Data Animal Data In an embryo-fetal development study in rats, pregnant animals receiving oral doses of idelalisib during the period of organogenesis (implantation to closure of the hard palate), embryo-fetal toxicities were observed at the mid- and high-doses that also resulted in maternal toxicity, based on reductions in maternal body weight gain.

Adverse findings at idelalisib doses ≥ 75 mg/kg/day included decreased fetal weights, external malformations (short tail), and skeletal variations (delayed ossification and/or unossification of the skull, vertebrae, and sternebrae). Additional findings were observed at 150 mg/kg/day dose of idelalisib and included urogenital blood loss, complete resorption, increased post-implantation loss, and malformations (vertebral agenesis with anury, hydrocephaly, and microphthalmia/anophthalmia). The dose of 75 and 150 mg/kg/day of idelalisib in rats resulted in exposures (AUC) of approximately 12 and 30 times, respectively, the human exposure at the recommended dose of 150 mg twice daily.

Pediatric Use Safety and effectiveness of Zydelig in pediatric patients have not been established.

Zydelig is contraindicated in patients with a history of serious hypersensitivity reactions to idelalisib, including anaphylaxis, or patients with a history of toxic epidermal necrolysis with any drug . History of serious hypersensitivity reactions to idelalisib, including anaphylaxis, or history of toxic epidermal necrolysis with any drug.