------------------DOSAGE FORMS AND STRENGTHS--------------------­
`Tablets: 150 mg, 100 mg. (3)
`----------------------------CONTRAINDICATIONS----------------------------­
`History of serious allergic reactions including anaphylaxis and toxic
`epidermal necrolysis. (4)
`---------------------WARNINGS AND PRECAUTIONS----------------------­
`
`
`
`• Severe cutaneous reactions: Monitor patients for the development of
`
`
`
`
`severe cutaneous reactions and discontinue Zydelig. (5.5)
`
`• Anaphylaxis: Monitor patients for anaphylaxis and discontinue
`
`
`Zydelig. (5.6)
`
`• Neutropenia: monitor blood counts. (5.7)
`
`
`
`
`• Embryo-fetal toxicity: may cause fetal harm. Advise women of
`
`
`
`
`
`potential risk to a fetus and to avoid pregnancy while taking Zydelig.
`
`
`(5.8)
`
`---------------------------ADVERSE REACTIONS----------------------------­
`
`
`The most common adverse reactions (incidence ≥20%) are diarrhea,
`
`
`
`
`pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills,
`
`
`
`and rash (6.1).
`
`
`The most common laboratory abnormalities (incidence ≥30%) are
`
`
`
`
`
`neutropenia, hypertriglyceridemia, hyperglycemia, ALT elevations, and
`
`
`
`
`
`AST elevations (6.1).
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Gilead
`
`
`
`Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch
`
`------------------------------DRUG INTERACTIONS--------------------------­
`
`• CYP3A inducers: Avoid coadministration of strong CYP3A inducers
`
`
`
`with Zydelig. (7.1)
`
`
`• CYP3A substrates: Avoid coadministration of CYP3A substrates
`
`
`
`
`
`with Zydelig. (7.2)
`
`
`------------------------USE IN SPECIFIC POPULATIONS-----------------­
`
`Nursing mothers: Discontinue drug or nursing. (8.3)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`Guide.
`
`
`
`
`
`
`
`
`
`Revised: 7/2014
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
`
` These highlights do not include all the information needed to use
` ZYDELIG safely and effectively. See full prescribing information
`
`
`
`
` for ZYDELIG.
` ZYDELIG® (idelalisib) tablets, for oral use
`
`
`
` Initial U.S. Approval: 2014
`
`
`
`
`
`
`
`
`
`
`WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC,
`
`SEVERE DIARRHEA, COLITIS, PNEUMONITIS, and INTESTINAL
`
`
`
`
`PERFORATION
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`
`• Fatal and/or serious hepatotoxicity occurred in 14% of Zydelig­
`
`
`
`
`
`treated patients. Monitor hepatic function prior to and during
`
`
`
`treatment. Interrupt and then reduce or discontinue Zydelig.
`
`
`
`(5.1)
`
`• Fatal and/or serious and severe diarrhea or colitis occurred in
`
`
`
`
`
`14% of Zydelig-treated patients. Monitor for the development
`
`
`
`
`
`of severe diarrhea or colitis. Interrupt and then reduce or
`
`
`
`
`
`discontinue Zydelig. (5.2)
`
`
`• Fatal and serious pneumonitis can occur in Zydelig-treated
`
`
`patients. Monitor for pulmonary symptoms and bilateral
`
`
`
`interstitial infiltrates. Interrupt or discontinue Zydelig. (5.3)
`
`
`• Fatal and serious intestinal perforation can occur in Zydelig­
`
`
`
`
`
`treated patients across clinical trials. Discontinue Zydelig if
`
`
`
`intestinal perforation is suspected. (5.4)
`
`
`
`
`
`
`
`
`------------------------INDICATIONS AND USAGE---------------------------
`
`
`Zydelig is a kinase inhibitor indicated for the treatment of patients with:
`
`
`
`• Relapsed chronic lymphocytic leukemia (CLL), in combination with
`
`
`
`rituximab, in patients for whom rituximab alone would be considered
`
`
`appropriate therapy due to other co-morbidities. (1.1)
`
`
`• Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients
`
`
`
`
`who have received at least two prior systemic therapies. (1.2)
`
`
`
`
`
`
`• Relapsed small lymphocytic lymphoma (SLL) in patients who have
`
`
`received at least two prior systemic therapies. (1.3)
`
`
`
`
`
`Accelerated approval was granted for FL and SLL based on overall
`
`response rate. Improvement in patient survival or disease related
`
`
`symptoms has not been established. Continued approval for these
`
`
`
`indications may be contingent upon verification of clinical benefit in
`
`
`confirmatory trials.
`
`
`---------------------DOSAGE AND ADMINISTRATION---------------------­
`
`
`Recommended starting dose: 150 mg orally, twice daily. (2.1)
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE
`
`
`
`
`
`DIARRHEA, COLITIS, PNEUMONITIS, and INTESTINAL
`
`
`
`PERFORATION
`
`1 INDICATIONS AND USAGE
`
`
`1.1 Relapsed Chronic Lymphocytic Leukemia
`
`
`
`1.2 Relapsed Follicular B-cell non-Hodgkin Lymphoma
`
`
`
`1.3 Relapsed Small Lymphocytic Lymphoma
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Recommended Dose
`
`
`2.2 Dose Modification
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Hepatotoxicity
`
`
`5.2 Severe Diarrhea or Colitis
`
`
`
`5.3 Pneumonitis
`
`
`5.4 Intestinal Perforation
`
`
`
`5.5 Severe Cutaneous Reactions
`
`
`5.6 Anaphylaxis
`
`
`
`5.7 Neutropenia
`
`
`
`5.8 Embryo-fetal Toxicity
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trial Experience
`
`
`7 DRUG INTERACTIONS
`
`7.1 Effects of Other Drugs on Zydelig
`
`
`
`7.2 Effects of Zydelig on Other Drugs
`
`
`
`
`
`Reference ID: 3597801
`
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`
`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Females of Reproductive Potential
`
`
`
`
`8.7 Renal Impairment
`
`
`
`8.8 Hepatic Impairment
`
`
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`
`13.2 Animal Pharmacology and/or Toxicology
`
`
`
`14 CLINICAL STUDIES
`
`14.1 Relapsed Chronic Lymphocytic Leukemia
`
`
`
`14.2 Relapsed Follicular B-cell non-Hodgkin Lymphoma
`
`
`14.3 Relapsed Small Lymphocytic Lymphoma
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`* Sections or subsections omitted from the full prescribing
`
`
`
`
`information are not listed.
`
`
`
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1038, p. 1 of 25
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
` WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA,
`
`
`
`
`
`
`
` COLITIS, PNEUMONITIS, and INTESTINAL PERFORATION
` • Fatal and/or serious hepatotoxicity occurred in 14% of Zydelig-treated
`
`
`
`
`
`
`patients. Monitor hepatic function prior to and during treatment. Interrupt and
`
` then reduce or discontinue Zydelig as recommended [see Dosage and
` Administration (2.2), Warnings and Precautions (5.1)].
`
`
`• Fatal and/or serious and severe diarrhea or colitis occurred in 14% of Zydelig­
`
`
`
`
`
`
`
`
`
`treated patients. Monitor for the development of severe diarrhea or colitis.
`
`Interrupt and then reduce or discontinue Zydelig as recommended [see
`
`Dosage and Administration (2.2), Warnings and Precautions (5.2)].
`
` • Fatal and serious pneumonitis can occur in Zydelig-treated patients. Monitor
`
`
`
` for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or
`
`
`discontinue Zydelig as recommended [see Dosage and Administration (2.2),
`
`
`Warnings and Precautions (5.3)].
`
`• Fatal and serious intestinal perforation can occur in Zydelig-treated patients
`
`
`
`across clinical trials. Discontinue Zydelig for intestinal perforation [see
`
`
`
`Warnings and Precautions (5.4)].
`
`
`
`
`
`1
`
`
`INDICATIONS AND USAGE
`
`
`
`1.1 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.
`
`
`1.2 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.
`
`
`
`
`1.3 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.
`
`
`
`
`
`Reference ID: 3597801
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1038, p. 2 of 25
`
`

`

`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.
`
`
`
`
`
`2
`
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1 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.
`
`
`2.2 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.
`
`
`
`Reference ID: 3597801
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1038, p. 3 of 25
`
`

`

`
`
`
`Dose Modifications for Toxicities Due to Zydelig
`Table 1
` Any symptomatic pneumonitis
`
`
` 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
`
`
`
`
` Diarrhea*
`
`
`
`
`
`
`
` Neutropenia
`
`
`
`
`Thrombocytopenia
`
`
`
`
`
` >1.5-3 x ULN
`
`
`
`
`
` >3-10 x ULN
`
`
`
` Maintain Zydelig dose.
`
`
`
` Monitor at least weekly
`
`
`
`
` until <1 x ULN.
`
`
`
`Moderate diarrhea
`
` Maintain Zydelig dose.
`
`
`
` Monitor at least weekly
`
`
`
` until resolved.
`
`
`
`
` Withhold Zydelig.
` Monitor at least weekly
`
`
`
`
`
`
` until bilirubin is <1 x
`ULN, then may resume
`
`
`
`Zydelig at 100 mg BID.
`
`
`
`
`Severe diarrhea or
`
`
`hospitalization
`
` Withhold Zydelig.
`
`
`
`
`
`
` Monitor at least weekly
` until resolved, then may
`
`
`
` resume Zydelig at 100
`
`
` mg BID.
`
`
`
`
`
`
`
`
`
`
` ANC 0.5 to <1.0 Gi/L
`
`
`
`
` ANC 1.0 to <1.5 Gi/L
`
`
` Maintain Zydelig dose. Maintain Zydelig dose.
`
`
`
` Monitor ANC at least
`
`weekly.
`
`
`
` >10 x ULN
`
`
`
`Discontinue Zydelig
`
`permanently.
`
`
`
`
`
`Life-threatening diarrhea
`
`Discontinue Zydelig
`
`permanently.
`
`
`
` ANC <0.5 Gi/L
`
`
`
`
` Interrupt Zydelig. Monitor
`
` ANC at least weekly until
`
`
` ANC ≥0.5 Gi/L, then may
`
`
`
` resume Zydelig at 100 mg
`
`
` BID.
`
`Platelets <25 Gi/L
`
`
`
`
`
`
`
`
`
`
` Platelets 50 to <75 Gi/L Platelets 25 to <50 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.
`
` 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.
`
`
`
`
`
`
`Reference ID: 3597801
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1038, p. 4 of 25
`
`

`

`
`
`
`
` 3
`
`
`
` 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.
`
`
`
`
` 4
`
`
`
` CONTRAINDICATIONS
`
`History of serious allergic reactions including anaphylaxis and toxic epidermal
`
`necrolysis.
`
`
`
`
` 5
`
`
`
` WARNINGS AND PRECAUTIONS
`
`
`
`5.1 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)].
`
`
`
`5.2 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)].
`
`
`
`
`5.3 Pneumonitis
`
`
`Fatal and serious pneumonitis occurred in patients treated with Zydelig. Patients taking
`
`
`
`
`Zydelig who present with pulmonary symptoms such as cough, dyspnea, hypoxia,
`
`
`
`
`
`
`Reference ID: 3597801
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1038, p. 5 of 25
`
`

`

`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
`5.4
`
`
`
`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.
`
`
`
`
`
`5.5 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.
`
`
`5.6 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.
`
`
`5.7 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)].
`
`
`
`
`
`5.8 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
`
`
`
`
`Reference ID: 3597801
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1038, p. 6 of 25
`
`

`

` during treatment, and for at least 1 month after the last dose of Zydelig [see Use in
`
`
`
` Specific Populations (8.6)].
`
`
`
`
`
`
`
` 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.
`
`
`
` • Hepatotoxicity [see Warnings and Precautions (5.1)]
`
`
` • Severe Diarrhea or Colitis [see Warnings and Precautions (5.2)]
`
`
`
`
` • Pneumonitis [see Warnings and Precautions (5.3)]
`
`
`
`
` Intestinal Perforation [see Warnings and Precautions (5.4)]
`
`•
`
` • Severe Cutaneous Reactions [see Warnings and Precautions (5.5)]
`
`
` • Anaphylaxis [see Warnings and Precautions (5.6)]
`
`
`
` • Neutropenia [see Warnings and Precautions (5.7)]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 6.1 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.
`
`
`
`
`
`
`
`
`Reference ID: 3597801
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1038, p. 7 of 25
`
`

`

`
` Table 2
`
`
`
`
`
`
`
` Adverse Reactions Reported in ≥5% of CLL Patients and Occurred at
`
`
`
`
`
`
` ≥2% Higher Incidence in Subjects Receiving Zydelig
` Placebo + R
` Zydelig + R
`
`
`
` N=108 (%)
`
` N=110 (%)
`Any Grade Grade ≥3
`Any Grade Grade ≥3
`
`
`
`
`
`
`
`
`
`Adverse Reaction
`
`
`Gastrointestinal disorders
`nausea
`
`vomiting
`
`diarrhea (a)
`
`gastroesophageal reflux disease
`
`stomatitis
`
`Nervous system disorders
`
`11 (10)
`headache
`
`
`
`General disorders and administration site conditions
`38 (35)
`pyrexia
`
`
`23 (21)
`chills
`
`
`pain
`8 (7)
`
`
`
`Skin and subcutaneous tissue disorders
`rash (b)
`
`
`Respiratory, thoracic, and mediastinal disorders
`
`
`pneumonia (c)
`
`
`nasal congestion
`
`Infections and infestations
`
`sepsis (d)
`
`bronchitis
`
`sinusitis
`
`urinary tract infection
`
`
`Musculoskeletal and connective tissue disorders
`
`8 (7)
`arthralgia
`
`
`
`
` (a) Diarrhea includes the following preferred terms: diarrhea, colitis.
`
` (b) Rash includes the following preferred terms: dermatitis exfoliative, rash, rash macular, rash maculo-papular, rash
`
`
` papular, rash pruritic, and skin disorder.
` (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) Sepsis includes the terms: sepsis, septic shock, neutropenic sepsis, and sepsis syndrome.
` R: rituximab
`
`
`
`
`
`28 (25)
`
`14 (13)
`
`
` 23 (21)
`7 (6)
`
`7 (6)
`
`
`0
`
`0
`
` 6 (5)
`0
`
`2 (2)
`
`
`
`
`23 (21)
`
`9 (8)
`
` 17 (16)
`1 (1)
`
`2 (2)
`
`
`
`
`1 (1)
`
`
`5 (5)
`
`
`3 (3)
`
`2 (2)
`
`0
`
`
`18 (17)
`
`17 (16)
`
`2 (2)
`
`
`
`
` 20 (18)
`
`
`
` 4 (4)
`
`
`
` 7 (6)
`
`0
`
`0
`
`
` 0
`0
`
`0
`
`
`0
`
`
`1 (1)
`
`0
`
`0
`
`
`
`
` 1 (1)
`
`
`
`
` 25 (23)
`6 (5)
`
`
`
` 9 (8)
`7 (6)
`
`9 (8)
`
`6 (5)
`
`
`
`
`
` 18 (16)
`0
`
`
`
`
`
` 19 (18)
`2 (2)
`
`
`
`
`
` 14 (13)
`0
`
`
`
` 8 (7)
`1 (1)
`
`0
`
`0
`
`
`
` 4 (4)
`3 (3)
`
`4 (4)
`
`3 (3)
`
`
`1 (1)
`
`
`4 (4)
`
`
`
`
`
` 4 (4)
`1 (1)
`
`0
`
`2 (2)
`
`
`1 (1)
`
`
`
`
`
`
`
`Reference ID: 3597801
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1038, p. 8 of 25
`
`

`

`
`
` Table 3
`
`
`
` Treatment-emergent Laboratory Abnormalities Reported in ≥10% of
`
`
`
`CLL Patients Occurring at a ≥5% Higher Incidence in Subjects
`Receiving Zydelig
`
`
`
`
`
`
`Laboratory Parameter
`
`
`Hematology abnormalities
`neutrophil count decreased
`
`
`lymphocyte count decreased
`
`lymphocyte count increased
`
`
`Serum chemistry abnormalities
`
`ALT increased
`
`AST increased
`
`GGT increased
`
`triglycerides (hypertriglyceridemia)
`
`hyperglycemia
`
`hypoglycemia
`
`hyponatremia
`
` Grades were obtained per CTCAE version 4.03.
`
` R: rituximab
`
`
`
`
`
`
` Placebo + R
` Zydelig + R
`
`
`
` N=110 (%)
` N=108 (%)
`Any Grade Grade 3–4 Any Grade Grade 3–4
`
`
`
`
`
`
`
`
`66 (60)
`22 (20)
`
`27 (25)
`
`
`
`38 (35)
`
`27 (25)
`29 (26)
`
`62 (56)
`
`59 (54)
`
`12 (11)
`
`22 (20)
`
`
`
`41 (37)
`10 (9)
`
`20 (18)
`
`
`
`9 (8)
`
`6 (5)
`2 (2)
`
`3 (3)
`
`8 (7)
`
`0
`
`2 (2)
`
`
`
`55 (51)
`13 (12)
`
`10 (9)
`
`
`
`11 (10)
`
`15 (14)
`15 (14)
`
`37 (34)
`
`50 (46)
`
`5 (5)
`
`16 (15)
`
`
`
`29 (27)
`4 (4)
`
`5 (5)
`
`
`
`1 (1)
`
`0
`3 (3)
`
`0
`
`2 (2)
`
`0
`
`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.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3597801
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1038, p. 9 of 25
`
`

`

`
`
` Table 4
`
`
`
`
`
`
` Adverse Reactions (≥ 10% of Subjects) in Patients with Indolent non-
`
` Hodgkin Lymphoma Treated with Zydelig 150 mg BID
`
`
`
`
`Zydelig Monotherapy
`N=146 (%)
`
`Grade ≥3
`
`
`Any Grade
`
`
`Adverse Reaction
`
`Gastrointestinal disorders
`
`diarrhea (a)
`
`nausea
`
`
`abdominal pain (b)
`
`
`
`vomiting
`
`
`General disorders and administration site conditions
`
`fatigue
`
`
`pyrexia
`
`
`asthenia
`
`
`peripheral edema
`
`
`Infections and infestations
`
`upper respiratory tract infection
`
`
`
`Respiratory, thoracic, and mediastinal disorders
`
`
`pneumonia (c)
`
`
`cough
`
`
`
`dyspnea
`
`
`Skin and subcutaneous disorders
`
`rash (d)
`
`
`night sweats
`
`
`Nervous system disorders
`
`
`headache
`
`
`Metabolism and nutrition disorders
`
`decreased appetite
`
`
`Psychiatric disorders
`
`0
`17 (12)
`insomnia
`
`
`
`
` (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.
`
`
` 68 (47)
`42 (29)
`
`
` 38 (26)
`22 (15)
`
`
`44 (30)
`
`41 (28)
`
`17 (12)
`
`15 (10)
`
`
`18 (12)
`
`
`
` 37 (25)
`42 (29)
`
`25 (17)
`
`
`
` 31 (21)
`18 (12)
`
`
`16 (11)
`
`
`24 (16)
`
`
`
`
` 20 (14)
`2 (1)
`
`
` 3 (2)
`2 (1)
`
`
`2 (1)
`
`3 (2)
`
`
`3 (2)
`
`3 (2)
`
`
`0
`
`
`
`
` 23 (16)
`1 (1)
`
`6 (4)
`
`
`
`
` 4 (3)
`0
`
`
`1 (1)
`
`
`1 (1)
`
`
`
`
`
`
`
`Reference ID: 3597801
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1038, p. 10 of 25
`
`

`

`
`
`Table 5
`
`
`
`
`
`
`
`Treatment-emergent Laboratory Abnormalities in Patients with
`
`
`
`
`Indolent non-Hodgkin Lymphoma Treated with Zydelig 150 mg BID
` Zydelig Monotherapy
`
`
` N=146 (%)
`
`
`Grade 3
`
`
`
`Any Grade
`
`
`
`Laboratory Abnormality
`
`Serum chemistry
`
`abnormalities
`
`ALT increased
`
`
`AST increased
`
`
`Hematology abnormalities
`
`78 (53)
`neutrophils decreased
`
`
`
`41 (28)
`hemoglobin decreased
`
`
`
`38 (26)
`platelets decreased
`
`
`
` Grades were obtained per CTCAE version 4.03.
`
`73 (50)
`
`60 (41)
`
`
`
`
`
`
` 7
`
`
`
` DRUG INTERACTIONS
`
`Grade 4
`
`
`
`20 (14)
`
`12 (8)
`
`
`
`20 (14)
`
`3 (2)
`
`4 (3)
`
`
`7 (5)
`
`6 (4)
`
`
`
`16 (11)
`
`0
`
`5 (3)
`
`
`
`
` 7.1 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)].
`
`
`
`
`
`
`
`
`
` 7.2 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)].
`
`
`Reference ID: 3597801
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1038, p. 11 of 25
`
`

`

`8
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1 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.
`
`
`8.3 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.
`
`
`
`8.4 Pediatric Use
`
`
`Safety and effectiveness of Zydelig in children less than 18 years of age have not been
`established.
`
`
`8.5 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
`
`
`
`
`
`Reference ID: 3597801
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1038, p. 12 of 25
`
`

`

`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
`8.6
`
`
`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)].
`
`
`
`8.7 Renal Impairment
`
`
`No dose adjustment of Zydelig is necessary for patients with creatinine clearance (CLcr)
`
`≥ 15 mL/min [see Clinical Pharmacology (12.3)].
`
`
`
`
`8.8 Hepatic Impairment
`
`
`The AUC of idelalisib increased up to 1.7-fold in subjects with ALT o