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Zydelig

Generic Name: idelalisib
Dosage Form: tablet, film coated

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, and INTESTINAL PERFORATION

Indications and Usage for Zydelig

Relapsed Chronic Lymphocytic Leukemia

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

Relapsed Follicular B-cell non-Hodgkin Lymphoma

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

Accelerated approval was granted for this indication based on Overall Response Rate [see Clinical Studies (14.2)]. 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.

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 [see Clinical Studies (14.3)]. 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.

Zydelig Dosage and Administration

Recommended Dose

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 the table below 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 life-threatening toxicities, reduce the dose to 100 mg twice daily. Recurrence of other severe or life-threatening Zydelig-related toxicity upon rechallenge should result in permanent discontinuation of Zydelig.

Table 1 Dose Modifications for Toxicities Due to Zydelig
Pneumonitis Any symptomatic pneumonitis
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; ULN, upper limit of normal
*
Moderate diarrhea: increase of 4–6 stools per day over baseline; severe diarrhea: increase of ≥7 stools per day over baseline.
Discontinue Zydelig in patients with any severity of symptomatic pneumonitis
ALT/AST >3–5 × ULN >5–20 × ULN >20 × ULN
Maintain Zydelig dose. Monitor at least weekly until ≤1 × ULN. Withhold Zydelig.
Monitor at least weekly until ALT/AST are ≤1 × ULN, then may resume Zydelig at 100 mg BID.
Discontinue Zydelig permanently.
Bilirubin >1.5–3 × ULN >3–10 × ULN >10 × ULN
Maintain Zydelig dose. Monitor at least weekly until ≤1 × ULN. Withhold Zydelig. Monitor at least weekly until bilirubin is ≤1 × ULN, then may resume Zydelig at 100 mg BID. Discontinue Zydelig permanently.
Diarrhea * Moderate diarrhea Severe diarrhea or hospitalization 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.

Dosage Forms and Strengths

150 mg tablets: pink, oval-shaped, film-coated tablet debossed with "GSI" on one side and "150" on the other side.

100 mg tablets: orange, oval-shaped, film-coated tablet debossed with "GSI" on one side and "100" on the other side.

Contraindications

History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis.

Warnings and Precautions

Hepatotoxicity

Fatal and/or serious hepatotoxicity occurred in 14% of patients treated with Zydelig. Elevations in ALT or AST greater than 5 times the upper limit of normal have occurred [see Adverse Reactions (6.1)]. These findings were generally observed within the first 12 weeks of treatment and were reversible with dose interruption. After resumption of treatment at a lower dose, 26% of patients had recurrence of ALT and AST elevations. Discontinue Zydelig for recurrent hepatotoxicity.

Avoid concurrent use of Zydelig with other drugs that may cause liver toxicity.

Monitor ALT and AST in all patients every 2 weeks for the first 3 months of treatment, every 4 weeks for the next 3 months, then every 1 to 3 months thereafter. Monitor weekly for liver toxicity if the ALT or AST rises above 3 times the upper limit of normal until resolved. Withhold Zydelig if the ALT or AST is greater than 5 times the upper limit of normal, and continue to monitor AST, ALT and total bilirubin weekly until the abnormality is resolved [see Dosage and Administration (2.2)].

Severe Diarrhea or Colitis

Severe diarrhea or colitis (Grade 3 or higher) occurred in 14% of Zydelig-treated patients across clinical trials [see Adverse Reactions (6.1)]. Diarrhea can occur at any time. Avoid concurrent use of Zydelig and other drugs that cause diarrhea. Diarrhea due to Zydelig responds poorly to antimotility agents. Median time to resolution ranged between 1 week and 1 month across trials, following interruption of Zydelig therapy and in some instances, use of corticosteroids [see Dosage and Administration (2.2)].

Pneumonitis

Fatal and serious pneumonitis occurred in patients treated with Zydelig. Patients taking Zydelig who present with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic exam, or a decline by more than 5% in oxygen saturation should be evaluated for pneumonitis. If pneumonitis is suspected, interrupt Zydelig until the etiology of the pulmonary symptoms has been determined. Patients with pneumonitis thought to be caused by Zydelig have been treated with discontinuation of Zydelig and administration of corticosteroids.

Intestinal Perforation

Fatal and serious intestinal perforation occurred in Zydelig-treated patients. At the time of perforation, some patients had moderate to severe diarrhea. Advise patients to promptly report any new or worsening abdominal pain, chills, fever, nausea, or vomiting. Discontinue Zydelig permanently in patients who experience intestinal perforation.

Severe Cutaneous Reactions

One case of toxic epidermal necrolysis (TEN) occurred in a study of Zydelig in combination with rituximab and bendamustine. Other severe or life-threatening (Grade ≥3) cutaneous reactions, including dermatitis exfoliative, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, exfoliative rash, and skin disorder, have been reported in Zydelig-treated patients. Monitor patients for the development of severe cutaneous reactions and discontinue Zydelig.

Anaphylaxis

Serious allergic reactions, including anaphylaxis, have been reported in patients on Zydelig. In patients who develop serious allergic reactions, discontinue Zydelig permanently and institute appropriate supportive measures.

Neutropenia

Treatment-emergent Grade 3 or 4 neutropenia occurred in 31% of Zydelig-treated patients across clinical trials [see Adverse Reactions (6.1)]. Monitor blood counts at least every two weeks for the first 3 months of therapy, and at least weekly in patients while neutrophil counts are less than 1.0 Gi/L [see Dosage and Administration (2.2)].

Embryo-fetal Toxicity

Based on findings in animals, Zydelig may cause fetal harm when administered to a pregnant woman. Idelalisib is teratogenic in rats, at systemic exposures 12 times those reported in patients at the recommended dose of 150 mg twice daily. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Advise females of reproductive potential to avoid becoming pregnant while taking Zydelig. If contraceptive methods are being considered, use effective contraception during treatment, and for at least 1 month after the last dose of Zydelig [see Use in Specific Populations (8.6)].

Adverse Reactions

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.

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 subject exposure to Zydelig from Study 1, in which 218 subjects with relapsed CLL received up to 8 doses of rituximab with or without Zydelig 150 mg twice daily. The median duration of exposure to Zydelig was 5 months.

Serious adverse reactions were reported in 54 (49%) subjects treated with Zydelig + rituximab. The most frequent (≥2%) serious adverse reactions reported for subjects treated with Zydelig were pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%) and diarrhea (5%). Adverse reactions that led to discontinuation of Zydelig occurred in 11 (10%) subjects. The most common adverse reactions that led to treatment discontinuations were hepatotoxicity and diarrhea/colitis.

Thirty-nine subjects (35%) had dose interruptions and sixteen subjects (15%) had dose reductions due to adverse reactions or laboratory abnormalities. The most common reasons for dose reductions were elevated transaminases, diarrhea or colitis, and rash.

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

Table 2 Adverse Reactions Reported in ≥5% of CLL Patients and Occurred at ≥2% Higher Incidence in Subjects Receiving Zydelig
Zydelig + R
N=110 (%)
Placebo + R
N=108 (%)
Adverse Reaction Any Grade Grade ≥3 Any Grade Grade ≥3
R: rituximab
*
Diarrhea includes the following preferred terms: diarrhea, colitis.
Rash includes the following preferred terms: dermatitis exfoliative, rash, rash macular, rash maculo-papular, rash papular, rash pruritic, and skin disorder.
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.
§
Sepsis includes the terms: sepsis, septic shock, neutropenic sepsis, and sepsis syndrome.
Gastrointestinal disorders
  nausea 28 (25) 0 23 (21) 0
  vomiting 14 (13) 0 9 (8) 0
  diarrhea * 23 (21) 6 (5) 17 (16) 0
  gastroesophageal reflux disease 7 (6) 0 1 (1) 0
  stomatitis 7 (6) 2 (2) 2 (2) 0
Nervous system disorders
  headache 11 (10) 1 (1) 5 (5) 0
General disorders and administration site conditions
  pyrexia 38 (35) 3 (3) 18 (17) 1 (1)
  chills 23 (21) 2 (2) 17 (16) 0
  pain 8 (7) 0 2 (2) 0
Skin and subcutaneous tissue disorders
  rash 20 (18) 4 (4) 7 (6) 1 (1)
Respiratory, thoracic, and mediastinal disorders
  pneumonia 25 (23) 18 (16) 19 (18) 14 (13)
  nasal congestion 6 (5) 0 2 (2) 0
Infections and infestations
  sepsis § 9 (8) 8 (7) 4 (4) 4 (4)
  bronchitis 7 (6) 1 (1) 3 (3) 1 (1)
  sinusitis 9 (8) 0 4 (4) 0
  urinary tract infection 6 (5) 0 3 (3) 2 (2)
Musculoskeletal and connective tissue disorders
  arthralgia 8 (7) 1 (1) 4 (4) 1 (1)
Table 3 Treatment-emergent Laboratory Abnormalities Reported in ≥10% of CLL Patients Occurring at a ≥5% Higher Incidence in Subjects Receiving Zydelig
Zydelig + R
N=110 (%)
Placebo + R
N=108 (%)
Laboratory Parameter Any Grade Grade 3–4 Any Grade Grade 3–4
Grades were obtained per CTCAE version 4.03.
R: rituximab
Hematology abnormalities
  neutrophil count decreased 66 (60) 41 (37) 55 (51) 29 (27)
  lymphocyte count decreased 22 (20) 10 (9) 13 (12) 4 (4)
  lymphocyte count increased 27 (25) 20 (18) 10 (9) 5 (5)
Serum chemistry abnormalities
  ALT increased 38 (35) 9 (8) 11 (10) 1 (1)
  AST increased 27 (25) 6 (5) 15 (14) 0
  GGT increased 29 (26) 2 (2) 15 (14) 3 (3)
  triglycerides (hypertriglyceridemia) 62 (56) 3 (3) 37 (34) 0
  hyperglycemia 59 (54) 8 (7) 50 (46) 2 (2)
  hypoglycemia 12 (11) 0 5 (5) 0
  hyponatremia 22 (20) 2 (2) 16 (15) 7 (6)

Summary of Clinical Trials in Indolent Non-Hodgkin Lymphoma

The safety data reflect exposure to Zydelig in 146 adults with indolent non-Hodgkin lymphoma treated with Zydelig 150 mg twice daily in clinical trials. The median duration of exposure was 6.1 months (range 0.3 to 26.4 months).

Serious adverse reactions were reported in 73 (50%) subjects. 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%) subjects. 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 subjects receiving Zydelig monotherapy, and Table 5 provides the treatment-emergent laboratory abnormalities.

Table 4 Adverse Reactions (≥ 10% of Subjects) in Patients with Indolent non-Hodgkin Lymphoma Treated with Zydelig 150 mg BID
Zydelig Monotherapy
N=146 (%)
Adverse Reaction Any Grade Grade ≥3
*
Diarrhea includes the following preferred terms: diarrhea, colitis, enterocolitis, and gastrointestinal inflammation.
Abdominal pain includes the following preferred terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.
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.
§
Rash includes the following preferred terms: dermatitis exfoliative, rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, and exfoliative rash.
Gastrointestinal disorders
  diarrhea * 68 (47) 20 (14)
  nausea 42 (29) 2 (1)
  abdominal pain 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)
Infections and infestations
  upper respiratory tract infection 18 (12) 0
Respiratory, thoracic, and mediastinal disorders
  pneumonia 37 (25) 23 (16)
  cough 42 (29) 1 (1)
  dyspnea 25 (17) 6 (4)
Skin and subcutaneous disorders
  rash § 31 (21) 4 (3)
  night sweats 18 (12) 0
Nervous system disorders
  headache 16 (11) 1 (1)
Metabolism and nutrition disorders
  decreased appetite 24 (16) 1 (1)
Psychiatric disorders
  insomnia 17 (12) 0
Table 5 Treatment-emergent Laboratory Abnormalities in Patients with Indolent non-Hodgkin Lymphoma Treated with Zydelig 150 mg BID
Zydelig Monotherapy
N=146 (%)
Laboratory Abnormality Any Grade Grade 3 Grade 4
Grades were obtained per CTCAE version 4.03.
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)

Drug Interactions

Effects of Other Drugs on Zydelig

CYP3A Inducers

The AUC of idelalisib was reduced by 75% when Zydelig was coadministered with a strong CYP3A inducer. Avoid coadministration of Zydelig with strong CYP3A inducers, such as rifampin, phenytoin, St. John's wort, or carbamazepine [see Clinical Pharmacology (12.3)].

CYP3A Inhibitors

The AUC of idelalisib was increased 1.8-fold when Zydelig was coadministered with a strong CYP3A inhibitor [see Clinical Pharmacology (12.3)]. If patients are taking concomitant strong CYP3A inhibitors, monitor for signs of Zydelig toxicity [see Warnings and Precautions (5)]. Follow dose modifications for adverse reactions [see Dosage and Administration (2.2)].

Effects of Zydelig on Other Drugs

CYP3A Substrates

Zydelig is a strong CYP3A inhibitor. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when Zydelig was coadministered with a sensitive CYP3A substrate. Avoid coadministration of Zydelig with CYP3A substrates [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.8)]

Risk Summary

Based on findings in animals, Zydelig may cause fetal harm when administered to a pregnant woman. Idelalisib was teratogenic in animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Animal Data

In an embryo-fetal development study, pregnant rats were administered oral doses of idelalisib during the period of organogenesis at 25, 75, and 150 mg/kg/day. 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.

Nursing Mothers

It is not known whether idelalisib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Zydelig, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of Zydelig in children less than 18 years of age have not been established.

Geriatric Use

In clinical trials of Zydelig in patients with FL, SLL, and CLL, 131/208 (63%) patients were age 65 and older. No major differences in effectiveness were observed. In patients 65 years of age or older with indolent non-Hodgkin lymphoma in comparison to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (28% vs 20%), higher incidence of serious adverse reactions (64% vs 37%), and higher incidence of death (11% vs 5%). In patients 65 years of age or older with CLL in comparison to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (11% vs 5%), higher incidence of serious adverse reactions (51% vs 43%), and higher incidence of death (3% vs 0%).

Females of Reproductive Potential

Contraception

Zydelig may cause fetal harm when administered during pregnancy. Advise females of reproductive potential to avoid becoming pregnant while taking Zydelig. If contraceptive methods are being considered, use effective contraception while taking Zydelig and for at least one month after taking the last dose of Zydelig. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking Zydelig [see Use in Specific Populations (8.1)].

Renal Impairment

No dose adjustment of Zydelig is necessary for patients with creatinine clearance (CLcr) ≥ 15 mL/min [see Clinical Pharmacology (12.3)].

Hepatic Impairment

The AUC of idelalisib increased up to 1.7-fold in subjects with ALT or AST or bilirubin greater than the upper limit of normal (ULN) compared to healthy subjects with normal ALT or AST or bilirubin values [see Clinical Pharmacology (12.3)]. Safety and efficacy data are not available in patients with baseline ALT or AST values greater than 2.5 × ULN or bilirubin values greater than 1.5 × ULN, as these patients were excluded from Studies 1 and 2. Patients with baseline hepatic impairment should be monitored for signs of Zydelig toxicity [see Warnings and Precautions (5)]. Follow dose modifications for adverse reactions [see Dosage and Administration (2.2)].

Zydelig Description

Idelalisib is an inhibitor of phosphatidylinositol 3-kinase, PI3Kδ.

The chemical name for idelalisib is 5-fluoro-3-phenyl-2-[(1S)-1-( 9H-purin-6-ylamino)propyl]quinazolin-4( 3H)-one. It has a molecular formula of C 22H 18FN 7O and a molecular weight of 415.42 g/mol. Idelalisib has the following structural formula:

Idelalisib is a white to off-white solid with a pH-dependent aqueous solubility ranging from <0.1 mg/mL at pH 5–7 to over 1 mg/mL at pH 2 under ambient conditions.

Zydelig (idelalisib) tablets are for oral administration. Each tablet contains either 100 mg or 150 mg of idelalisib with the following inactive ingredients: microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, magnesium stearate and a tablet coating. The tablet coating consists of polyethylene glycol, talc, polyvinyl alcohol, and titanium dioxide and of FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake (for the 100 mg tablet) and red iron oxide (for the 150 mg tablet).

Zydelig - Clinical Pharmacology

Mechanism of Action

Idelalisib is an inhibitor of PI3Kδ kinase, which is expressed in normal and malignant B-cells. Idelalisib induced apoptosis and inhibited proliferation in cell lines derived from malignant B-cells and in primary tumor cells. Idelalisib inhibits several cell signaling pathways, including B-cell receptor (BCR) signaling and the CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B-cells to the lymph nodes and bone marrow. Treatment of lymphoma cells with idelalisib resulted in inhibition of chemotaxis and adhesion, and reduced cell viability.

Pharmacodynamics

Electrocardiographic Effects

The effect of Zydelig (150 mg and 400 mg) on the QT/QTc interval was evaluated in a placebo- and positive-controlled (moxifloxacin 400 mg) crossover study in 46 healthy subjects. At a dose 2.7 times the maximum recommended dose, Zydelig did not prolong the QT/QTc interval (i.e., not greater than or equal to 10 ms).

Pharmacokinetics

Absorption

Following oral administration of a single dose of Zydelig in the fasted state, the median T max was observed at 1.5 hours.

Idelalisib exposure increased in a less than dose-proportional manner over a dose range of 50 mg to 350 mg twice daily in the fasted state.

Relative to fasting conditions, the administration of a single dose of Zydelig with a high-fat meal increased idelalisib AUC 1.4-fold. Zydelig can be administered without regard to food.

Distribution

Idelalisib is greater than 84% bound to human plasma proteins with no concentration dependence. The mean blood-to-plasma ratio was 0.7. The population apparent central volume of distribution at steady state is 23 L.

Metabolism and Elimination

Idelalisib is metabolized to its major metabolite GS-563117 via aldehyde oxidase and CYP3A. GS-563117 is inactive against PI3Kδ in vitro. Idelalisib undergoes minor metabolism by UGT1A4.

The population apparent systemic clearance at steady-state is 14.9 L/hr. The population terminal elimination half-life of idelalisib is 8.2 hours. Following a single dose of 150 mg of [ 14C] idelalisib, 78% and 14% of the radioactivity was excreted in feces and urine, respectively. GS-563117 accounted for 49% of the radioactivity in the urine and 44% in the feces.

Specific Populations

Age, Gender, Race, and Weight

Population pharmacokinetic analyses indicated that age, gender, race, and weight had no effect on idelalisib exposure.

Pediatric Patients

The pharmacokinetics of idelalisib has not been studied in pediatric patients.

Patients with Renal Impairment

A pharmacokinetic study following a single dose of 150 mg of Zydelig was performed in healthy subjects and subjects with severe renal impairment (CLcr 15 to 29 mL/min). Creatinine clearance had no effect on idelalisib exposure. No dose adjustment is needed for patients with CLcr ≥15 mL/min.

Patients with Hepatic Impairment

A pharmacokinetic study of Zydelig was performed in healthy subjects and subjects with hepatic impairment. The geometric mean AUC increased up to 1.7-fold in subjects with ALT or AST or bilirubin values greater than the upper limit of normal (ULN) compared to subjects with normal AST or ALT or bilirubin values. Limited safety and efficacy data are available for patients with baseline AST or ALT greater than 2.5 × ULN or bilirubin greater than 1.5 × ULN, as these patients were excluded from Studies 1 and 2. Patients with baseline hepatic impairment should be monitored for signs of Zydelig toxicity [see Boxed Warning and Warnings and Precautions (5.1)]. Follow dose modifications for adverse reactions [see Dosage and Administration (2.2)].

Drug Interactions

In Vitro Studies

Idelalisib is a substrate for aldehyde oxidase, CYP3A, and UGT1A4 in vitro.

Idelalisib inhibits CYP2C8, CYP2C19, CYP3A, and UGT1A1 and GS-563117 inhibits CYP2C8, CYP2C9, CYP2C19, CYP3A and UGT1A1 in vitro. Idelalisib and GS-563117 are not likely to inhibit CYP1A, CYP2B6, and CYP2D6.

Idelalisib induces CYP2B6 and CYP3A4, but does not induce CYP1A2 in vitro. GS-563117 does not induce these enzymes.

Idelalisib and GS-563117 are substrates of P-glycoprotein (P-gp) and BCRP in vitro. Idelalisib is not a substrate of OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. GS-563117 is not a substrate of OATP1B1 or OATP1B3.

Idelalisib inhibits P-gp, OATP1B1, and OATP1B3, and GS-563117 inhibits OATP1B1, OATP1B3 in vitro. Idelalisib is not likely to inhibit BCRP, OCT2, OAT1, or OAT3, and GS-563117 is not likely to inhibit P-gp, BCRP, OCT2, OAT1, or OAT3.

Effect of Other Drugs on Idelalisib

A single dose of 150 mg of Zydelig was administered alone and after rifampin (a strong CYP3A and P-gp inducer) 600 mg once daily for 8 days in healthy subjects. Rifampin decreased the geometric mean idelalisib AUC by 75% and the geometric mean C max by 58%. Avoid coadministration of Zydelig with strong CYP3A and P-gp inducers.

A single dose of 400 mg of Zydelig was administered alone and after ketoconazole (a strong CYP3A and P-gp inhibitor) 400 mg daily for 4 days in healthy subjects. Ketoconazole increased the geometric mean idelalisib AUC by 1.8-fold. No changes in the geometric mean C max were observed. Patients taking concomitant CYP3A inhibitors should be monitored for signs of Zydelig toxicity [see Warnings and Precautions (5)]. Follow dose modifications for adverse reactions [see Dosage and Administration (2.2)].

Effect of Idelalisib on Other Drugs

A single oral dose of midazolam 5 mg was administered alone and after Zydelig 150 mg for 15 doses in healthy subjects. The geometric mean midazolam Cmax increased by 2.4-fold and the geometric mean midazolam AUC increased by 5.4-fold. Avoid coadministration of Zydelig with CYP3A substrates, as Zydelig is a strong CYP3A inhibitor.

A single dose of 10 mg of rosuvastatin (OATP1B1 and OATP1B3 substrate) was administered alone and after Zydelig 150 mg for 12 doses in healthy subjects. No changes in exposure to rosuvastatin were observed.

A single dose of 0.5 mg of digoxin (P-gp substrate) was administered alone and after Zydelig 150 mg for 19 doses in healthy subjects. No changes in exposure to digoxin were observed.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with idelalisib have not been conducted.

Idelalisib did not induce mutations in the bacterial mutagenesis (Ames) assay and was not clastogenic in the in vitro chromosome aberration assay using human peripheral blood lymphocytes. Idelalisib was genotoxic in males in the in vivo rat micronucleus study at a high dose of 2000 mg/kg.

Idelalisib may impair fertility in humans. In a fertility study, treated male rats (25, 50, or 100 mg/kg/day of idelalisib) were mated with untreated females. Decreased epididymidal and testicular weights were observed at all dose levels and reduced sperm concentration at the mid- and high doses; however, there were no adverse effects on fertility parameters. The low dose in males resulted in an exposure (AUC) that is approximately 50% of the exposure in patients at the recommended dose of 150 mg twice daily.

In a separate fertility study, treated female rats (25, 50, or 100 mg/kg/day of idelalisib) were mated with untreated males. There were no adverse effects on fertility parameters; however, there was a decrease in the number of live embryos at the high dose. The high dose in females resulted in an exposure (AUC) that is approximately 17-fold the exposure in patients at the recommended dose of 150 mg twice daily.

Animal Pharmacology and/or Toxicology

Toxicities observed in animals and not reported in patients include cardiac toxicity (cardiomyopathy, inflammation, and increased heart weight) and pancreatic findings (inflammation, hemorrhage, and low-incidence acinar degeneration and hyperplasia). These findings were observed in Sprague-Dawley rats in toxicology studies at exposures (AUCs) higher than those reported in patients at the recommended dose of 150 mg twice daily. Cardiac inflammation was mainly seen in a 28-day study in rats, the other findings were observed in the 13-week and/or 6-month studies.

Clinical Studies

Relapsed Chronic Lymphocytic Leukemia

Zydelig was evaluated in a randomized, double-blind, placebo-controlled study (Study 1) in 220 subjects with relapsed CLL who required treatment and were unable to tolerate standard chemoimmunotherapy due to coexisting medical conditions, reduced renal function as measured by creatinine clearance <60 mL/min, or NCI CTCAE Grade ≥3 neutropenia or Grade ≥3 thrombocytopenia resulting from myelotoxic effects of prior therapy with cytotoxic agents. Subjects were randomized 1:1 to receive 8 doses of rituximab (first dose at 375 mg/m 2, subsequent doses at 500 mg/m 2 every 2 weeks for 4 infusions and every 4 weeks for an additional 4 infusions) in combination with either an oral placebo twice daily or with Zydelig 150 mg taken twice daily until disease progression or unacceptable toxicity.

In Study 1, the median age was 71 (range 47, 92) with 78% over 65, 66% were male, and 90% were Caucasian. The median time since diagnosis was 8.5 years. The median number of prior therapies was 3. Nearly all (96%) subjects had received prior anti-CD20 monoclonal antibodies. The most common (>15%) prior regimens were: bendamustine + rituximab (98 subjects, 45%), fludarabine + cyclophosphamide + rituximab (75 subjects, 34%), single-agent rituximab (67 subjects, 31%), fludarabine + rituximab (37 subjects, 17%), and chlorambucil (36 subjects, 16%).

The primary endpoint was progression free survival (PFS), as assessed by an independent review committee (IRC). The trial was stopped for efficacy following the first pre-specified interim analysis. Results of a second interim analysis continued to show a statistically significant improvement for Zydelig + rituximab over placebo + rituximab for the primary endpoint of PFS (HR: 0.18, 95% CI [0.10, 0.32], p < 0.0001). The efficacy results are shown in Table 6 and the Kaplan-Meier curve for PFS is shown in Figure 1.

Table 6 Efficacy Results from Study 1
Zydelig + R
n=110
Placebo + R
n=110
R: rituximab; PFS: progression-free survival; NR: not reached
*
The p value for PFS was based on stratified log-rank test.
PFS Median (months) (95% CI) NR (10.7, NR) 5.5 (3.8, 7.1)
Hazard ratio (95% CI) 0.18 (0.10, 0.32)
P-value < 0.0001 *

Figure 1 Kaplan-Meier Plot of Study 1 IRC-Assessed PFS

Relapsed Follicular B-cell non-Hodgkin Lymphoma

The safety and efficacy of Zydelig in patients with FL was evaluated in a single-arm, multicenter clinical trial which included 72 patients with follicular B-cell non-Hodgkin lymphoma who had relapsed within 6 months following rituximab and an alkylating agent and had received at least 2 prior treatments. The median age was 62 years (range 33 to 84), 54% were male, and 90% were Caucasian. At enrollment, 92% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 4.7 years and the median number of prior treatments was 4 (range 2 to 12). The most common prior combination regimens were R-CHOP (49%), BR (50%), and R-CVP (28%). At baseline, 33% of patients had extranodal involvement and 26% had bone marrow involvement.

Patients received 150 mg of Zydelig orally twice daily until evidence of disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group response criteria for malignant lymphoma. The primary endpoint was Independent Review Committee-assessed overall response rate (ORR). Efficacy results are summarized in Table 7.

Table 7 Overall Response Rate (ORR) and Duration of Response (DOR) in Patients with Relapsed Follicular Lymphoma
N=72
CI = confidence interval; CR = complete response; PR = partial response
*
Kaplan-Meier estimate
ORR 39 (54%)
  95% CI (42, 66%)
  CR 6 (8%)
  PR 33 (46%)
Median * DOR, months (range) median not evaluable (0.0+, 14.8+)

The median time to response was 1.9 months (range 1.6–8.3).

Relapsed Small Lymphocytic Lymphoma

The safety and efficacy of Zydelig in patients with SLL was evaluated in a single-arm, multicenter clinical trial which included 26 patients with small lymphocytic lymphoma who had relapsed within 6 months following rituximab and an alkylating agent and had received at least 2 prior treatments. The median age was 65 years (range 50 to 87), 73% were male, and 81% were Caucasian. At enrollment, 96% of patients had a baseline ECOG performance status of 0 or 1. The median time since diagnosis was 6.7 years and the median number of prior treatments was 4 (range 2 to 9). The most common prior combination regimens were BR (81%), FCR (62%) and R-CHOP (35%). At baseline, 27% of patients had extranodal involvement.

Subjects received 150 mg of Zydelig orally twice daily until evidence of disease progression or unacceptable toxicity. Tumor response was assessed according to the revised International Working Group response criteria for malignant lymphoma. The primary endpoint was Independent Review Committee-assessed overall response rate (ORR). Efficacy results are summarized in Table 8.

Table 8 Overall Response Rate (ORR) and Duration of Response (DOR) in Patients with Relapsed Small Lymphocytic Lymphoma
N=26
CI = confidence interval; CR = complete response; PR = partial response
*
Kaplan-Meier estimate
ORR 15 (58%)
  95% CI (37, 77%)
  CR 0
  PR 15 (58%)
Median * DOR, months (range) 11.9 (0.0+, 14.7+)

The median time to response was 1.9 months (range 1.6–8.3).

How Supplied/Storage and Handling

Zydelig tablets supplied as follows:

Tablet Strength Package Configuration NDC No. Description of Tablet; Debossed on Tablet
150 mg High density polyethylene (HDPE) bottle with a polyester fiber coil, capped with a child-resistant closure. Each bottle contains 60 film-coated tablets. 61958-1702-1 Oval shaped; pink; "150" on one side and "GSI" on the other side
100 mg 61958-1701-1 Oval-shaped; orange; "100" on one side and "GSI" on the other side  

Store between 20–30 °C (68–86 °F) with excursions permitted 15–30 ºC (59–86 ºF).

  • Dispense only in original container.
  • Do not use if seal over bottle opening is broken or missing.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling ( Medication Guide).

Physicians and health care professionals are advised to discuss the following with patients prior to treatment with Zydelig:

•     Hepatotoxicity

Advise patients that Zydelig can cause significant elevations in liver enzymes, and that serial testing of serum liver tests (ALT, AST, and bilirubin) are recommended while taking Zydelig [see Warnings and Precautions (5.1)]. Advise patients to report symptoms of liver dysfunction including jaundice, bruising, abdominal pain, or bleeding.

•     Severe Diarrhea or Colitis

Advise patients that Zydelig may cause severe diarrhea or colitis and to notify their healthcare provider immediately if the number of bowel movements in a day increases by six or more [see Warnings and Precautions (5.2)].

•     Pneumonitis

Advise patients of the possibility of pneumonitis, and to report any new or worsening respiratory symptoms including cough or dyspnea [see Warnings and Precautions (5.3)].

•     Intestinal Perforation

Advise patients of the possibility for intestinal perforation and to notify their healthcare provider immediately if they experience severe abdominal pain [see Warnings and Precautions (5.4)].

•     Severe Cutaneous Reactions

Advise patients that Zydelig may cause severe cutaneous reactions and to notify their healthcare provider immediately if they develop a severe skin reaction [see Warnings and Precautions (5.5)].

•     Anaphylaxis

Advise patients that anaphylaxis can occur during treatment with Zydelig and to notify their healthcare provider immediately if they experience symptoms of anaphylaxis [see Warnings and Precautions (5.6)].

•     Neutropenia

Advise patients of the need for periodic monitoring of blood counts. Advise patients to notify their healthcare provider immediately if they develop a fever or any signs of infection [see Warnings and Precautions (5.7)].

•     Pregnancy and Nursing

Advise women of the potential hazard to the fetus and to avoid pregnancy during treatment with Zydelig. If contraceptive methods are being considered, advise to use adequate contraception during therapy and for at least one month after completing therapy. Also advise patients not to breastfeed while taking Zydelig [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1, 8.3, and 8.6)].

•     Instructions for Taking Zydelig

Advise patients to take Zydelig exactly as prescribed and not to change their dose or to stop taking Zydelig unless they are told to do so by their healthcare provider. Zydelig may be taken with or without food. Zydelig tablets should be swallowed whole. Advise patients that if a dose of Zydelig is missed by less than 6 hours, to take the missed dose right away and take the next dose as usual. If a dose of Zydelig is missed by more than 6 hours, advise patients to wait and take the next dose at the usual time.

Manufactured and distributed by:

Gilead Sciences, Inc.

Foster City, CA 94404

GSI and Zydelig are trademarks or registered trademarks of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners.

©2014 Gilead Sciences, Inc. All rights reserved.

205858-GS-000-PI

MEDICATION GUIDE

Zydelig ® (zye-DEL-ig)
(idelalisib) tablets

Read this Medication Guide before you start taking Zydelig and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment.

What is the most important information I should know about Zydelig?

Zydelig can cause serious side effects that can lead to death, including:

  • Liver problems. Your doctor will do blood tests before and during your treatment with Zydelig to check for liver problems. Tell your doctor right away if you get any of the following symptoms of liver problems:
    • yellowing of your skin or the white part of your eyes (jaundice)
    • dark or brown (tea colored) urine
    • pain in the upper right side of your stomach area (abdomen)
    • bleeding or bruising more easily than normal
  • Severe diarrhea. Diarrhea is common with Zydelig and can sometimes be severe. Tell your doctor right away if the number of bowel movements you have in a day increases by six or more. Ask your doctor about medicines you can take to treat your diarrhea.
  • Lung or breathing problems. Your doctor may do tests to check your lungs if you have breathing problems during treatment with Zydelig. Tell your doctor right away if you get new or worsening cough, shortness of breath, difficulty breathing, or wheezing.
  • Tear in intestinal wall (perforation). Tell your doctor or get medical help right away if you get new or worsening stomach area (abdomen) pain, chills, fever, nausea, or vomiting.

If you have any of the above serious side effects during treatment with Zydelig, your doctor may completely stop your treatment, stop your treatment for a period of time, or change your dose of Zydelig.

See " What are the possible side effects of Zydelig?" for more information about side effects.

What is Zydelig?

Zydelig is a prescription medicine used to treat people with:

  • Chronic Lymphocytic Lymphoma (CLL) in combination with rituximab when CLL comes back after prior cancer treatment when rituximab treatment alone may be used due to other health problems.
  • Follicular B-cell non-Hodgkin Lymphoma (FL) when the disease has come back after treatment with at least two prior medicines.
  • Small Lymphocytic Lymphoma (SLL) when the disease comes back after treatment with at least two prior medicines.

It is not known if Zydelig is safe and effective in children less than 18 years of age.

What should I tell my doctor before taking Zydelig? Before taking Zydelig, tell your doctor about all of your medical conditions, including if you:

  • have liver problems
  • have lung or breathing problems
  • are pregnant or plan to become pregnant. Zydelig may harm your unborn baby. Females who are able to become pregnant should use effective birth control (contraception) during treatment with Zydelig and for 1 month after stopping treatment. Talk to your doctor about birth control methods that may be right for you. Tell your doctor right away if you become pregnant during treatment with Zydelig.
  • are breastfeeding or plan to breastfeed. It is not known if Zydelig passes into your breast milk. You and your doctor should decide if you will take Zydelig or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Zydelig and certain other medicines may affect each other. Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

How should I take Zydelig?

  • Take Zydelig exactly as your doctor tells you to take it.
  • Your doctor may change your dose of Zydelig or tell you to stop taking Zydelig. Do not change your dose or stop taking Zydelig without first talking to your doctor.
  • Take Zydelig 2 times a day.
  • You may take Zydelig with or without food.
  • Take Zydelig tablets whole.
  • Do not miss a dose of Zydelig. If you miss a dose of Zydelig by less than 6 hours, take the missed dose right away. Then take your next dose as usual. If you miss a dose of Zydelig by more than 6 hours, wait and take the next dose of Zydelig at your usual time.

What are the possible side effects of Zydelig?

Zydelig can cause serious side effects, including:

  • See " What is the most important information I should know about Zydelig?"
  • Severe skin reactions. Tell your doctor if you get any of the following symptoms during treatment with Zydelig:
    • painful sores or ulcers on your skin, lips, or in your mouth
    • severe rash with blisters or peeling skin
  • Anaphylaxis. Tell your doctor or get medical help right away if you have a serious allergic reaction while taking Zydelig.
  • Low white blood cell count (neutropenia). Your doctor will check your blood counts regularly during treatment with Zydelig. Tell your doctor right away if you have a fever or any signs of an infection while taking Zydelig.

The most common side effects of Zydelig include fever, feeling tired, nausea, cough, stomach area (abdomen) pain, and chills.

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Zydelig. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Zydelig?

  • Store Zydelig between 68°F to 86°F (20°C to 30°C).
  • Keep Zydelig in its original container.
  • Do not use Zydelig if the seal over the bottle opening is broken or missing.

Keep Zydelig and all medicines out of reach of children.

General information about Zydelig

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Zydelig for a condition for which it was not prescribed. Do not give Zydelig to other people, even if they have the same symptoms you have. It may harm them. You can ask your doctor or pharmacist for information about Zydelig that is written for health professionals.

What are the ingredients in Zydelig?

Active ingredient: idelalisib

Inactive ingredients: microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, and magnesium stearate.

The tablet coating contains polyethylene glycol, talc, polyvinyl alcohol, titanium dioxide and FD&C Yellow #6/Sunset Yellow (for the 100 mg tablet) and red iron oxide (for the 150 mg tablet).

Manufactured and distributed by: Gilead Sciences, Inc. Foster City, CA 94404
©2014 Gilead Sciences, Inc. All rights reserved
For more information, call 1-800-445-3235 or go to www.Zydelig.com.
205858-GS-000-MG

This Medication Guide has been approved by the U.S. Food and Drug Administration.
Issued: July 2014

PRINCIPAL DISPLAY PANEL - 100 mg Tablet Bottle Label

NDC 61958- 1701-1
60 tablets

Zydelig ®
(idelalisib) Tablets

100 mg

DISPENSER: Each time Zydelig ® is dispensed
give the patient the attached Medication Guide.

PRINCIPAL DISPLAY PANEL - 150 mg Tablet Bottle Label

NDC 61958- 1702-1
60 tablets

Zydelig ®
(idelalisib) Tablets

150 mg

DISPENSER: Each time Zydelig ® is dispensed
give the patient the attached Medication Guide.

Zydelig 
idelalisib tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:61958-1701
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
IDELALISIB (IDELALISIB) IDELALISIB 100 mg
Inactive Ingredients
Ingredient Name Strength
CELLULOSE, MICROCRYSTALLINE  
HYDROXYPROPYL CELLULOSE (TYPE H)  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
CROSCARMELLOSE SODIUM  
MAGNESIUM STEARATE  
POLYVINYL ALCOHOL  
TITANIUM DIOXIDE  
POLYETHYLENE GLYCOLS  
TALC  
FD&C YELLOW NO. 6  
ALUMINUM OXIDE  
Product Characteristics
Color orange Score no score
Shape OVAL Size 10mm
Flavor Imprint Code GSI;100
Contains         
Packaging
# Item Code Package Description
1 NDC:61958-1701-1 60 TABLET, FILM COATED in 1 BOTTLE, PLASTIC
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA205858 07/23/2014
Zydelig 
idelalisib tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:61958-1702
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
IDELALISIB (IDELALISIB) IDELALISIB 150 mg
Inactive Ingredients
Ingredient Name Strength
CELLULOSE, MICROCRYSTALLINE  
HYDROXYPROPYL CELLULOSE (TYPE H)  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
CROSCARMELLOSE SODIUM  
MAGNESIUM STEARATE  
POLYVINYL ALCOHOL  
TITANIUM DIOXIDE  
POLYETHYLENE GLYCOLS  
TALC  
FERRIC OXIDE RED  
Product Characteristics
Color pink Score no score
Shape OVAL Size 10mm
Flavor Imprint Code GSI;150
Contains         
Packaging
# Item Code Package Description
1 NDC:61958-1702-1 60 TABLET, FILM COATED in 1 BOTTLE, PLASTIC
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA205858 07/23/2014
Labeler - Gilead Sciences, Inc. (185049848)
Revised: 09/2015
 
Gilead Sciences, Inc.
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