Zydelig (idelalisib)

Relapsed Chronic Lymphocytic Leukemia

Zydelig is indicated, in combination withrituximab, for the treatment of patients with relapsedchronic lymphocytic leukemia(CLL) for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.

Limitation Of Use

Zydelig is not indicated and is not recommended for first line treatment of patients with CLL.

Relapsed Follicular B-cell Non-Hodgkin Lymphoma

Zydelig is indicated for the treatment of patients with relapsed follicular B-cell non- Hodgkinlymphoma(FL) who have received at least two prior systemic therapies.

Accelerated approval was granted for this indication based on Overall Response Rate. An improvement in patient survival or disease related symptoms has not been established. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

Limitation Of Use

Zydelig is not indicated and is not recommended for first line treatment of patients with FL.

Zydelig is not indicated and is not recommended in combination with bendamustine and/or rituximab for the treatment of FL.

Relapsed Small Lymphocytic Lymphoma

Zydelig is indicated for the treatment of patients with relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies.

Accelerated approval was granted for this indication based on Overall Response Rate. An improvement in patient survival or disease related symptoms has not been established. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

Limitation Of Use

Zydelig is not indicated and is not recommended for first line treatment of patients with SLL.

The following serious adverse reactions have been associated with Zydelig inclinical trialsand 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 werepneumonia(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

• diarrhea (55%),
• pyrexia (38%),
• nausea(34%), and
• fatigue(34%).

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.
• 在研究313 - 0125年(NCT01732926), 475名患者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)

Recommended Dosage

• The recommended maximum starting dose of Zydelig is 150 mg administered orally twice daily.
• Zydelig can be taken with or without food. Tablets should be swallowed whole.
• Continue treatment until disease progression or unacceptable toxicity. The optimal and safe dosing regimen for patients who receive treatment longer than several months is unknown.

Dose Modification

See Table 1 for dose modification instructions for specific toxicities related to Zydelig. For other severe or life-threatening toxicities related to Zydelig, withhold drug until toxicity is resolved. If resuming Zydelig after interruption for other severe or lifethreatening toxicities, reduce the dose to 100 mg twice daily. Discontinue Zydelig permanently for recurrence of other severe or life-threatening Zydelig-related toxicity upon rechallenge.

Table 1 : Dose Modifications for Toxicities Due to Zydelig

Pneumonitis	Any symptomatic pneumonitis
	Discontinue Zydelig in patients with any severity of symptomatic pneumonitis
ALT/AST	>3-5 x ULN	>5-20 x ULN	>20 x ULN
	Maintain Zydelig dose. Monitor at least weekly until ≤1 x ULN.	Withhold Zydelig. Monitor at least weekly until ALT/AST are ≤1 x ULN, then may resume Zydelig at 100 mg BID.	Discontinue Zydelig permanently.
Bilirubin	>1.5-3 x ULN	>3-10 x ULN	>10 x ULN
	Maintain Zydelig dose. Monitor at least weekly until ≤1 x ULN.	Withhold Zydelig. Monitor at least weekly until bilirubin is ≤1 x ULN, then may resume Zydelig at 100 mg BID.	Discontinue Zydelig permanently.
Diarrhea*	Moderate diarrhea	严重的腹泻或住院治疗	Life-threatening diarrhea
	Maintain Zydelig dose. Monitor at least weekly until resolved.	Withhold Zydelig. Monitor at least weekly until resolved, then may resume Zydelig at 100 mg BID.	Discontinue Zydelig permanently.
Neutropenia	ANC 1.0 to <1.5 Gi/L	ANC 0.5 to <1.0 Gi/L	ANC <0.5 Gi/L
	Maintain Zydelig dose.	Maintain Zydelig dose. Monitor ANC at least weekly.	Interrupt Zydelig. Monitor ANC at least weekly until ANC ≥0.5 Gi/L, then may resume Zydelig at 100 mg BID.
Thrombocytopenia	Platelets 50 to <75 Gi/L	Platelets 25 to <50 Gi/L	Platelets <25 Gi/L
	Maintain Zydelig dose.	Maintain Zydelig dose. Monitor platelet counts at least weekly.	Interrupt Zydelig. Monitor platelet count at least weekly. May resume Zydelig at 100 mg BID when platelets ≥25 Gi/L.
Infections	Grade 3 or higher sepsis or pneumonia
	Interrupt Zydelig until infection has resolved.
	Evidence of CMV infection or viremia
	Interrupt Zydelig in patients with evidence of active CMV infection of any grade or viremia (positive PCR or antigen test) until the viremia has resolved. If Zydelig is resumed, monitor patients by PCR or antigen test for CMV reactivation at least monthly.
	Evidence of PJP infection
	Interrupt Zydelig in patients with suspected PJP infection of any grade. Permanently discontinue Zydelig if PJP infection is confirmed.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; ULN, upper limit of normal; CMV, cytomegalovirus; PCR: polymerase chain reaction; PJP: Pneumocystis jirovecii pneumonia *Moderate diarrhea: increase of 4–6 stools per day over baseline; severe diarrhea: increase of ≥7 stools per day over baseline.

不需要剂量修改淋巴球增多, which has been observed in some patients taking Zydelig. This observed lymphocytosis is a pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical findings.

Effects Of Other Drugs On Zydelig

Table 6 lists the potential effects of the coadministration of strong CYP3A modulators on Zydelig.

Table 6 :Drug Interactionswith 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.

• Based on findings in animal studies (see Data) and the mechanism of action, Zydelig may cause fetal harm when administered to apregnantwoman.
• There are no available data in pregnant women to inform the drug-associated risk.
• No data are available regarding the presence of idelalisib or its metabolites inhuman milkor its effects on thebreastfedchild or on milk production.
• Because of the potential for serious adverse reactions from Zydelig in a breastfed child, advise lactating women not to breastfeed while taking Zydelig and for at least 1 month after the last dose.