BOXED WARNING SECTION.

WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, and INTESTINAL PERFORATION. Fatal and/or serious hepatotoxicity occurred in 16% to 18% 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% to 20% 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/or serious pneumonitis occurred in 4% of 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/or serious infections occurred in 21% to 48% of Zydelig-treated patients. Monitor for signs and symptoms of infection. Interrupt Zydelig if infection is suspected [see Dosage and Administration (2.2), Warnings and Precautions (5.4)]. Fatal and serious intestinal perforation can occur in Zydelig-treated patients across clinical trials. Discontinue Zydelig for intestinal perforation [see Warnings and Precautions (5.5)].. WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, and INTESTINAL PERFORATIONSee full prescribing information for complete boxed warning.Fatal and/or serious hepatotoxicity occurred in 16% to 18% 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% to 20% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig. (5.2)Fatal and/or serious pneumonitis occurred in 4% of Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig. (5.3)Fatal and/or serious infections occurred in 21% to 48% of Zydelig-treated patients. Monitor for signs and symptoms of infection. Interrupt Zydelig if infection is suspected. (5.4)Fatal and serious intestinal perforation can occur in Zydelig-treated patients across clinical trials. Discontinue Zydelig if intestinal perforation is suspected. (5.5). Fatal and/or serious hepatotoxicity occurred in 16% to 18% 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% to 20% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig. (5.2). Fatal and/or serious pneumonitis occurred in 4% of Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig. (5.3). Fatal and/or serious infections occurred in 21% to 48% of Zydelig-treated patients. Monitor for signs and symptoms of infection. Interrupt Zydelig if infection is suspected. (5.4). Fatal and serious intestinal perforation can occur in Zydelig-treated patients across clinical trials. Discontinue Zydelig if intestinal perforation is suspected. (5.5).

INDICATIONS & USAGE SECTION.

1INDICATIONS AND USAGE. Zydelig is 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)Limitations of use:Zydelig is not indicated and is not recommended for first-line treatment of any patient. (1.1, 1.2, 1.3)Zydelig is not indicated and is not recommended in combination with bendamustine and/or rituximab for the treatment of FL. (1.2)FL and SLL are approved under accelerated approval 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.. 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). 1.1Relapsed 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.. Limitations of UseZydelig is not indicated and is not recommended for first line treatment of patients with CLL.. 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.This indication is approved under accelerated approval 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. Limitations of UseZydelig 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.. 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.This indication is approved under accelerated approval 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.. Limitations of UseZydelig is not indicated and is not recommended for first line treatment of patients with SLL.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 10/2020MEDICATION GUIDEZYDELIG(R) (zye-DEL-ig)(idelalisib)tabletsWhat is the most important information should know about ZydeligZydelig can cause serious side effects that can lead to death, including:Liver problems. Abnormal liver blood test results are common during treatment with Zydelig. Zydelig can cause severe 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) urinepain in the upper right side of your stomach area (abdomen)bleeding or bruising more easily than normal Severe diarrhea. Diarrhea is common during treatment with Zydelig and can sometimes be severe. Tell your doctor right away if the number of bowel movements you have in day increases by six or more. Ask your doctor about medicines you can take to treat your diarrhea.Lung problems (pneumonitis). 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. Your doctor may treat you with corticosteroid medicine if you develop lung problems.Infections. Zydelig can cause serious infections that may lead to death. Tell your doctor right away if you have fever or any signs of an infection during treatment with Zydelig.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.Severe skin reactions. Tell your doctor right away if you get any of the following symptoms during treatment with Zydelig:painful sores or ulcers on your skin, lips, or in your mouthsevere rash with blisters or peeling skinrash with itchingfeverenlarged lymph nodes 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 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 prescription medicine used to treat people with: Chronic Lymphocytic Leukemia (CLL) in combination with rituximab when CLL comes back after prior cancer treatment and 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.Zydelig should not be used as the first medicine to treat people with CLL, FL, or SLL.Zydelig should not be used in combination with bendamustine and or rituximab to treat people with FL.It is not known if Zydelig is safe and effective in children less than 18 years of age.Do not take Zydelig if you:have had serious allergic reaction to idelalisib.have had severe skin reaction called toxic epidermal necrolysis (TEN) to any drug.Before taking Zydelig, tell your doctor about all of your medical conditions, including if you:have liver problemshave lung problemshave an infectionare pregnant or plan to become pregnant. Zydelig may harm your unborn baby. Females who are able to become pregnant should have pregnancy test before starting treatment with Zydelig.Females who are able to become pregnant should use effective birth control (contraception) during treatment with Zydelig and for at least month after the last dose of Zydelig. Talk to your doctor about birth control methods that may be right for you. Tell your doctor right away if you become pregnant or think you are pregnant during treatment with Zydelig.Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with Zydelig and for months after the last dose. are breastfeeding or plan to breastfeed. It is not known if Zydelig passes into your breast milk. Do not breastfeed during your treatment with Zydelig and for at least month after the last dose.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 list of your medicines and show it to your doctor and pharmacist when you get new medicine.How should take ZydeligTake 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 times day. You may take Zydelig with or without food.Take Zydelig tablets whole.Do not miss dose of Zydelig. If you miss dose of Zydelig by less than hours, take the missed dose right away. Then take your next dose as usual. If you miss dose of Zydelig by more than hours, wait and take the next dose of Zydelig at your usual time.What are the possible side effects of ZydeligZydelig can cause serious side effects, including: See What is the most important information should know about Zydelig Anaphylaxis. Tell your doctor or get medical help right away if you have an allergic reaction during treatment with Zydelig.Low white blood cell count (neutropenia). Neutropenia is common during treatment with Zydelig and can sometimes be severe. Your doctor will check your blood counts regularly during treatment with Zydelig. Tell your doctor right away if you have fever or any signs of an infection during treatment with Zydelig.The most common side effects of Zydelig when used alone include:tirednessnauseacoughfeverstomach area (abdomen) painpneumoniarashThe most common side effects of Zydelig when used in combination with rituximab include:pneumoniafevertirednessrashcoughnauseaTell 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 store ZydeligStore Zydelig between 68F to 86F (20C to 30C).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 the safe and effective use of Zydelig.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use Zydelig for 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 ZydeligActive 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 or Sunset Yellow FCF Aluminum Lake (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(C)2020 Gilead Sciences, Inc. All rights reserved For more information, call 1-800-445-3235 or go to www.Zydelig.com.205858-GS-004-MG. Liver problems. Abnormal liver blood test results are common during treatment with Zydelig. Zydelig can cause severe 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) urinepain in the upper right side of your stomach area (abdomen)bleeding or bruising more easily than normal 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 during treatment with Zydelig and can sometimes be severe. Tell your doctor right away if the number of bowel movements you have in day increases by six or more. Ask your doctor about medicines you can take to treat your diarrhea.. Lung problems (pneumonitis). 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. Your doctor may treat you with corticosteroid medicine if you develop lung problems.. Infections. Zydelig can cause serious infections that may lead to death. Tell your doctor right away if you have fever or any signs of an infection during treatment with Zydelig.. 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.. Severe skin reactions. Tell your doctor right away if you get any of the following symptoms during treatment with Zydelig:painful sores or ulcers on your skin, lips, or in your mouthsevere rash with blisters or peeling skinrash with itchingfeverenlarged lymph nodes painful sores or ulcers on your skin, lips, or in your mouth. severe rash with blisters or peeling skin. rash with itching. fever. enlarged lymph nodes. Chronic Lymphocytic Leukemia (CLL) in combination with rituximab when CLL comes back after prior cancer treatment and 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.. have had serious allergic reaction to idelalisib.. have had severe skin reaction called toxic epidermal necrolysis (TEN) to any drug.. have liver problems. have lung problems. have an infection. are pregnant or plan to become pregnant. Zydelig may harm your unborn baby. Females who are able to become pregnant should have pregnancy test before starting treatment with Zydelig.Females who are able to become pregnant should use effective birth control (contraception) during treatment with Zydelig and for at least month after the last dose of Zydelig. Talk to your doctor about birth control methods that may be right for you. Tell your doctor right away if you become pregnant or think you are pregnant during treatment with Zydelig.Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with Zydelig and for months after the last dose. Females who are able to become pregnant should use effective birth control (contraception) during treatment with Zydelig and for at least month after the last dose of Zydelig. Talk to your doctor about birth control methods that may be right for you. Tell your doctor right away if you become pregnant or think you are pregnant during treatment with Zydelig.. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with Zydelig and for months after the last dose.. are breastfeeding or plan to breastfeed. It is not known if Zydelig passes into your breast milk. Do not breastfeed during your treatment with Zydelig and for at least month after the last dose.. 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 times day. You may take Zydelig with or without food.. Take Zydelig tablets whole.. Do not miss dose of Zydelig. If you miss dose of Zydelig by less than hours, take the missed dose right away. Then take your next dose as usual. If you miss dose of Zydelig by more than hours, wait and take the next dose of Zydelig at your usual time.. See What is the most important information should know about Zydelig Anaphylaxis. Tell your doctor or get medical help right away if you have an allergic reaction during treatment with Zydelig.. Low white blood cell count (neutropenia). Neutropenia is common during treatment with Zydelig and can sometimes be severe. Your doctor will check your blood counts regularly during treatment with Zydelig. Tell your doctor right away if you have fever or any signs of an infection during treatment with Zydelig.. tiredness. nausea. cough. fever. stomach area (abdomen) pain. pneumonia. rash. pneumonia. fever. tiredness. rash. cough. nausea. Store Zydelig between 68F to 86F (20C to 30C).. Keep Zydelig in its original container.. Do not use Zydelig if the seal over the bottle opening is broken or missing.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings in animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], Zydelig may cause fetal harm when administered to pregnant woman.There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of idelalisib to pregnant rats during organogenesis resulted in decreased fetal weight and congenital malformations in rats at maternal exposures (AUC) 12 times those reported in patients at the recommended dosage of 150 mg twice daily (see Data).The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies 2-4% and 15-20%, respectively.. Data. Animal DataIn an embryo-fetal development study in rats, pregnant animals receiving oral doses of idelalisib during the period of organogenesis (implantation to closure of the hard palate), embryo-fetal toxicities were observed at the mid- and high-doses that also resulted in maternal toxicity, based on reductions in maternal body weight gain. Adverse findings at idelalisib doses >= 75 mg/kg/day included decreased fetal weights, external malformations (short tail), and skeletal variations (delayed ossification and/or unossification of the skull, vertebrae, and sternebrae). Additional findings were observed at 150 mg/kg/day dose of idelalisib and included urogenital blood loss, complete resorption, increased post-implantation loss, and malformations (vertebral agenesis with anury, hydrocephaly, and microphthalmia/anophthalmia). The dose of 75 and 150 mg/kg/day of idelalisib in rats resulted in exposures (AUC) of approximately 12 and 30 times, respectively, the human exposure at the recommended dose of 150 mg twice daily.. 8.2 Lactation. Risk SummaryThere are no data on the presence of idelalisib or its metabolites in human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with Zydelig and for at least month after the last dose.. 8.3 Females and Males of Reproductive Potential. Zydelig may cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. PregnancyPregnancy testing is recommended for females of reproductive potential prior to starting Zydelig.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with Zydelig and for at least month after the last dose.. MalesAdvise males with female partners of reproductive potential to use effective contraception during treatment with Zydelig and for months after the last dose [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. Safety and effectiveness of Zydelig in pediatric patients have not been established.. 8.5 Geriatric Use. In clinical trials of Zydelig in 615 patients with FL, SLL, and CLL, 327 (53%) patients were aged 65 years and older. No overall differences in effectiveness were observed between these patients and younger patients. When comparing patients 65 years of age or older to younger patients with indolent non-Hodgkin lymphoma, older patients had 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%). When comparing patients 65 years of age or older to younger patients with CLL, older patients had higher incidence of discontinuation due to an adverse reaction (36% vs 28%), higher incidence of serious adverse reactions (73% vs 67%), and higher incidence of death (13% vs 9%).. 8.6 Hepatic Impairment. No dose adjustment is recommended for patients with ALT or AST or bilirubin upper limit of normal (ULN); however, limited safety and efficacy data are available for patients with baseline AST or ALT 2.5 ULN or bilirubin 1.5 ULN. Monitor patients with baseline hepatic impairment for adverse reactions [see Warnings and Precautions (5)]. Follow dosage modifications for adverse reactions [see Dosage and Administration (2.2)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Severe Cutaneous Reactions: Monitor patients for the development of severe cutaneous reactions. Permanently discontinue Zydelig if confirmed. (2.2, 5.6)Hypersensitivity Reactions: Permanently discontinue Zydelig and institute appropriate supportive measures. (2.2, 5.7)Neutropenia: Monitor blood counts. Interrupt Zydelig until resolution and resume at reduced dose. (2.2, 5.8)Embryo-fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of potential risk to fetus and to use effective contraception. (5.9, 8.1, 8.3). Severe Cutaneous Reactions: Monitor patients for the development of severe cutaneous reactions. Permanently discontinue Zydelig if confirmed. (2.2, 5.6). Hypersensitivity Reactions: Permanently discontinue Zydelig and institute appropriate supportive measures. (2.2, 5.7). Neutropenia: Monitor blood counts. Interrupt Zydelig until resolution and resume at reduced dose. (2.2, 5.8). Embryo-fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of potential risk to fetus and to use effective contraception. (5.9, 8.1, 8.3). 5.1 Hepatotoxicity. Fatal and/or serious hepatotoxicity occurred in 18% of patients treated with Zydelig monotherapy and 16% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies. Elevations in ALT or AST greater than 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 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 weeks for the first months of treatment, every weeks for the next months, then every to months thereafter. Monitor weekly for liver toxicity if the ALT or AST rises above times the upper limit of normal until resolved. Withhold Zydelig if the ALT or AST is greater than 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 or higher) occurred in 14% of patients treated with Zydelig monotherapy and 20% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies [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 week and 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. Clinical manifestations included interstitial infiltrates and organizing pneumonia. In randomized clinical trials of combination therapies, pneumonitis occurred in 4% of patients treated with Zydelig compared to 1% on the comparator arms. Time to onset of pneumonitis ranged from <1 to 15 months. Monitor patients on Zydelig for pulmonary symptoms. In patients taking Zydelig who present with pulmonary symptoms such as cough, dyspnea, hypoxia, interstitial infiltrates on radiologic exam, or decline by more than 5% in oxygen saturation, interrupt Zydelig until the etiology has been determined.If symptomatic pneumonitis or organizing pneumonia is diagnosed, initiate appropriate treatment with corticosteroids and permanently discontinue Zydelig [see Dosage and Administration (2.2)].. 5.4 Infections. Fatal and/or serious infections occurred in 21% of patients treated with Zydelig monotherapy and 48% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies [see Adverse Reactions (6.1)]. The most common infections were pneumonia, sepsis, and febrile neutropenia. Treat infections prior to initiation of Zydelig therapy. Monitor patients on Zydelig for signs and symptoms of infection, and interrupt Zydelig for Grade or higher infection [see Dosage and Administration (2.2)].Serious or fatal Pneumocystis jirovecii pneumonia (PJP) or cytomegalovirus (CMV) occurred in <1% of patients treated with Zydelig. Provide PJP prophylaxis during treatment with Zydelig. Interrupt Zydelig in patients with suspected PJP infection of any grade, and permanently discontinue Zydelig if PJP infection of any grade is confirmed. Regular clinical and laboratory monitoring for CMV infection is recommended in patients with history of CMV infection or positive CMV serology at the start of treatment with Zydelig. Interrupt Zydelig in the setting of positive CMV PCR or antigen test until the viremia has resolved. If Zydelig is subsequently resumed, patients should be monitored by PCR or antigen test for CMV reactivation at least monthly [see Dosage and Administration (2.2)].. 5.5 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.. 5.6 Severe Cutaneous Reactions. Fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have occurred in patients treated with Zydelig. Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have also occurred. Zydelig is contraindicated in patients with history of toxic epidermal necrolysis [see Contraindications (4)]. If SJS, TEN, or DRESS is suspected, interrupt Zydelig until the etiology of the reaction has been determined. If SJS, TEN, or DRESS is confirmed, permanently discontinue Zydelig [see Dosage and Administration (2.2)].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 patients treated with Zydelig. Monitor patients for the development of other severe or life-threatening cutaneous reactions and permanently discontinue Zydelig [see Dosage and Administration (2.2)].. 5.7 Hypersensitivity Reactions. Serious hypersensitivity reactions, including anaphylaxis, have been reported in patients on Zydelig. Zydelig is contraindicated in patients with history of serious hypersensitivity reactions to idelalisib, including anaphylaxis [see Contraindications (4)]. In patients who develop serious hypersensitivity reactions, permanently discontinue Zydelig [see Dosage and Administration (2.2)] and institute appropriate supportive measures.. 5.8 Neutropenia. Grade or neutropenia occurred in 25% of patients treated with Zydelig monotherapy and 58% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies. Monitor blood counts at least every weeks for the first months of therapy, and at least weekly in patients while neutrophil counts are less than 1.0 Gi/L. Interrupt Zydelig until resolution and resume at reduced dose [see Dosage and Administration (2.2)]. 5.9 Embryo-fetal Toxicity. Based on findings in animals and its mechanism of action, Zydelig may cause fetal harm when administered to pregnant woman. In animal reproduction studies, administration of idelalisib to pregnant rats during organogenesis caused decreased fetal weight and congenital malformations at systemic exposures 12 times those reported in patients at the recommended dose of 150 mg twice daily.Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with Zydelig and for at least month after the last dose [see Use in Specific Populations (8.1, 8.3)].

ADVERSE REACTIONS SECTION.

6ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling.Hepatotoxicity [see Warnings and Precautions (5.1)] Severe Diarrhea or Colitis [see Warnings and Precautions (5.2)] Pneumonitis [see Warnings and Precautions (5.3)] Infections [see Warnings and Precautions (5.4)] Intestinal Perforation [see Warnings and Precautions (5.5)] Severe Cutaneous Reactions [see Warnings and Precautions (5.6)] Hypersensitivity Reactions [see Warnings and Precautions (5.7)] Neutropenia [see Warnings and Precautions (5.8)] Hepatotoxicity [see Warnings and Precautions (5.1)] Severe Diarrhea or Colitis [see Warnings and Precautions (5.2)] Pneumonitis [see Warnings and Precautions (5.3)] Infections [see Warnings and Precautions (5.4)] Intestinal Perforation [see Warnings and Precautions (5.5)] Severe Cutaneous Reactions [see Warnings and Precautions (5.6)] Hypersensitivity Reactions [see Warnings and Precautions (5.7)] Neutropenia [see Warnings and Precautions (5.8)] The most common adverse reactions (incidence >=20%) in patients treated with Zydelig in the monotherapy trial are diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash. (6.1)The most common adverse reactions (incidence >=30%) in patients treated with Zydelig in combination trials are diarrhea, pneumonia, pyrexia, fatigue, rash, cough, and nausea. (6.1)Common laboratory abnormalities include neutropenia, 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.. The most common adverse reactions (incidence >=20%) in patients treated with Zydelig in the monotherapy trial are diarrhea, fatigue, nausea, cough, pyrexia, abdominal pain, pneumonia, and rash. (6.1). The most common adverse reactions (incidence >=30%) in patients treated with Zydelig in combination trials are diarrhea, pneumonia, pyrexia, fatigue, rash, cough, and nausea. (6.1). Common laboratory abnormalities include neutropenia, ALT elevations and AST elevations. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 LeukemiaThe 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 [see Clinical Studies (14.1)] and one randomized, open-label trial in 259 patients with relapsed CLL (Study 312-0119).. Zydelig with Rituximab (Study 312-0116)Patients with relapsed CLL received up to doses of rituximab (R) with or without Zydelig 150 mg twice daily. The median duration of exposure to Zydelig was 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 and Table summarize common adverse reactions and laboratory abnormalities reported for Zydelig R and placebo R arms.Table Adverse Reactions Reported in >=5% of Patients with CLL and Occurred at >=2% Higher Incidence in Patients Receiving Zydelig in Study 312-0116Zydelig RN=110 (%)Placebo RN=108 (%)Adverse ReactionAny GradeGrade >=3Any GradeGrade >=3General disorders and administration site conditions pyrexia44 (40)3 (3)20 (19)1 (1) chills27 (25)2 (2)17 (16)0 pain8 (7)01 (1)0Gastrointestinal disorders diarrhea Diarrhea includes the following preferred terms: diarrhea, colitis. 35 (32) 12 (11)20 (19)0 nausea30 (27)1 (1)25 (23)0 abdominal pain Abdominal pain includes the following preferred terms: abdominal pain, abdominal pain upper, abdominal pain lower. 20 (18)1 (1)17 (16)2 (2) vomiting 17 (15)09 (8)0 gastroesophageal reflux disease11 (10)1 (1)00 stomatitis7 (6)2 (2)1 (1)0Respiratory, thoracic, and mediastinal disorders pneumonia Pneumonia includes the terms: pneumonia, pneumonitis, lung infection, lung infiltration, pneumocystis jiroveci pneumonia, pneumonia legionella, lung infection pseudomonal, pneumonia fungal, respiratory tract infection, lower respiratory tract infection, and lower respiratory tract infection bacterial. 33 (30)23 (21)20 (19)14 (13)Skin and subcutaneous tissue disorders rash Rash includes the following preferred terms: dermatitis exfoliative, drug eruption, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash morbilliform, and exfoliative rash. 27 (25)4 (4)7 (6)1 (1)Metabolism and Nutrition Disorders decreased appetite18 (16)2 (2)12 (11)2 (2) dehydration7 (6)3 (3)00Infections and infestations sepsis Sepsis includes the terms: sepsis, septic shock, neutropenic sepsis, and sepsis syndrome 10 (9)10 (9)4 (4)4 (4) sinusitis (8)06 (6)0 urinary tract infection9 (8)1 (1)4 (4)2 (2) bronchitis (7)1 (1)5 (5)1 (1) oral herpes6 (5)1 (1)3 (3)0Psychiatric disorders insomnia10 (9)07 (6)0Musculoskeletal and connective tissue disorders arthralgia9 (8)1 (1)4 (4)0Nervous system disorders lethargy6 (5)02 (2)0Table Hematologic and Hepatic Laboratory Abnormalities Reported in >=10% of Patients with CLL and Occurred at >=5% Higher Incidence in Patients Receiving Zydelig in Study 312-0116Zydelig RN=110 (%)Placebo RN=108 (%)Laboratory ParameterAny GradeGrade 3-4Any GradeGrade 3-4Hematology abnormalities neutropenia71 (65)46 (42)61 (56)33 (31) leukopenia34 (31)9 (8)25 (23)9 (8) lymphocytopenia23 (21)11 (10)13 (12)4 (4)Serum chemistry abnormalities ALT increased43 (39)10 (9)13 (12)1 (1) AST increased31 (28)6 (5)16 (15)0After closure of Study 312-0116, 71 patients continued treatment with Zydelig on an extension study (Study 312-0117). The median duration of exposure was 18 months. Serious adverse reactions occurred in 48 (68%) patients. The most frequent serious adverse reactions reported were pneumonia (30%), diarrhea (15%), and pyrexia (11%).The most frequent adverse reactions were pneumonia (51%), pyrexia (46%), and cough (45%). The most frequent Grade or greater adverse reactions were pneumonia (30%), diarrhea (15%), and sepsis (10%).. Zydelig with Ofatumumab (Study 312-0119)In Study 312-0119, 259 patients with relapsed CLL received up to 12 doses of ofatumumab with or without Zydelig 150 mg orally twice daily. The median duration of exposure to Zydelig was 13.9 months.Serious adverse reactions were reported in 133 (77%) patients treated with Zydelig ofatumumab. The most frequent serious adverse reactions reported were pneumonia (14%), pyrexia (13%), and diarrhea (12%).Adverse reactions that led to discontinuation of Zydelig occurred in 71 (41%) patients.One hundred and ten (64%) patients had dose interruptions and 42 (24%) patients had dose reductions due to adverse reactions or laboratory abnormalities. The most common reasons for dose discontinuations, reductions, or interruptions were diarrhea and colitis.The most common adverse reactions were diarrhea (55%), pyrexia (38%), nausea (34%), and fatigue (34%).. Zydelig with Bendamustine and Rituximab (Study 312-0115)In Study 312-0115, patients with relapsed CLL received up to cycles of bendamustine and rituximab (BR) with or without Zydelig 150 mg orally twice daily. The median duration of exposure to Zydelig was 18.2 months.Serious adverse reactions were reported in 147 (71%) patients treated with Zydelig BR. The most frequent serious adverse reactions reported for patients treated with Zydelig BR were febrile neutropenia (21%), pneumonia (17%), pyrexia (12%), and diarrhea (6%).Adverse reactions that led to discontinuation of Zydelig occurred in 68 (33%) patients. The most common adverse reactions that led to treatment discontinuations were pneumonia, diarrhea, and pyrexia.One hundred twenty-two (59%) patients treated with Zydelig BR had dose interruptions and 34 (16%) patients had dose reductions due to adverse reactions. The most common reasons for dose interruptions or reductions were increased ALT and diarrhea.The most common adverse reactions were neutropenia (64%), pyrexia (43%), and diarrhea (41%).. Summary of Clinical Trials in Indolent Non-Hodgkin LymphomaThe safety data reflect exposure to Zydelig from three open-label clinical trials (Studies 101-09, 101-02, and 101-10 in 146 patients with indolent non-Hodgkin lymphoma (iNHL) treated with Zydelig 150 mg orally twice daily [see Clinical Studies (14.2, 14.3)]. 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 provides the adverse reactions occurring in at least 10% of patients receiving Zydelig monotherapy and Table provides the hematologic and hepatic laboratory abnormalities.Table Adverse Reactions Reported in >= 10% of Patients with Indolent NHL Treated with ZydeligZydelig MonotherapyN=146 (%)Adverse ReactionAny GradeGrade >=3Gastrointestinal disorders diarrhea Diarrhea includes the following preferred terms: diarrhea, colitis, enterocolitis, and gastrointestinal inflammation. 68 (47)20 (14) nausea42 (29)2 (1) abdominal pain Abdominal pain includes the following preferred terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. 38 (26)3 (2) vomiting22 (15)2 (1)General disorders and administration site conditions fatigue44 (30)2 (1) pyrexia41 (28)3 (2) asthenia17 (12)3 (2) peripheral edema15 (10)3 (2)Respiratory, thoracic, and mediastinal disorders cough42 (29)1 (1) pneumonia 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. 37 (25)23 (16) dyspnea25 (17)6 (4)Skin and subcutaneous disorders rash Rash includes the following preferred terms: dermatitis exfoliative, rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, and exfoliative rash. 31 (21)4 (3) night sweats18 (12)0Metabolism and nutrition disorders decreased appetite24 (16)1 (1)Infections and infestations upper respiratory tract infection18 (12)0Psychiatric disorders insomnia17 (12)0Nervous system disorders headache16 (11)1 (1)Table Hematologic and Hepatic Laboratory Abnormalities in Patients with Indolent non-Hodgkin Lymphoma Treated with ZydeligZydelig MonotherapyN=146 (%)Laboratory AbnormalityAny GradeGrade 3Grade 4Grades were obtained per CTCAE version 4.03.Serum chemistry abnormalities ALT increased73 (50)20 (14)7 (5) AST increased60 (41)12 (8)6 (4)Hematology abnormalities neutrophils decreased78 (53)20 (14)16 (11) hemoglobin decreased41 (28)3 (2)0 platelets decreased38 (26)4 (3)5 (3). Summary of Discontinued Clinical Trials in First-Line CLL and Early Line iNHLSafety data described below reflect exposure to Zydelig in three randomized, double-blind clinical trials (Studies 312-0123, 313-0124, and 313-0125) in patients with CLL and iNHL.In Study 312-0123 (NCT01980888), 311 patients with previously untreated CLL received up to cycles of BR with or without Zydelig 150 mg twice daily.In Study 313-0124 (NCT01732913), 295 patients with previously treated iNHL received doses of with or without Zydelig 150 mg twice daily. Patients had median of one prior therapy.In Study 313-0125 (NCT01732926), 475 patients with previously treated iNHL received up to cycles of BR with or without Zydelig 150 mg twice daily. Patients had median of two prior therapies.These three studies were terminated early due to higher incidence of fatal and/or serious adverse reactions observed in patients treated with Zydelig in combination with 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.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of Zydelig. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Skin and Subcutaneous Disorders Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Idelalisib is an inhibitor of phosphatidylinositol 3-kinase, PI3K, 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.. 12.2Pharmacodynamics. Cardiac ElectrophysiologyAt dose 2.7 times the maximum recommended dose, Zydelig did not prolong the QT/QTc interval (i.e., <=10 ms).. 12.3Pharmacokinetics. Idelalisib exposure increased in less than dose-proportional manner over dose range of 50 mg to 350 mg twice daily (0.3 to 2.3 times the approved recommended dosage).Following 150 mg twice daily administration of idelalisib, average (% coefficient of variation) maximum concentrations (Cmax) and area under the curve (AUC) at steady-state were 1861 (43%) ng/mL and 10598 (41%) ngh/mL for idelalisib.. AbsorptionThe median time to peak concentration (Tmax) was observed at 1.5 hours.. Food EffectThe administration of single dose of Zydelig with high-fat meal (900 calories: 525 calories fat, 250 calories carbohydrates, and 125 calories protein) increased idelalisib AUC 1.4-fold relative to fasting conditions.. DistributionProtein binding of idelalisib is >= 84% with no concentration dependence.The mean blood-to-plasma ratio was 0.7.The apparent central volume of distribution at steady state is 23 (%CV ~85%). Idelalisib is substrate of P-glycoprotein (P-gp) and BCRP in vitro.. EliminationThe population apparent systemic clearance at steady-state is 14.9 L/hr (%CV 38%). The population terminal elimination half-life of idelalisib is 8.2 hours.. MetabolismIdelalisib is metabolized via aldehyde oxidase and CYP3A with additional minor metabolism by UGT1A4.. ExcretionFollowing single 150 mg dose of radiolabeled idelalisib, 78% of the radioactivity was excreted in feces and 14% was excreted in the urine. Idelalisib is not substrate of OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.. Specific PopulationsAge (18 to 91 years), sex, race (White, and non-Whites), renal impairment (creatinine clearance >= 15 mL/min) and weight (38 to 148 kg) had no effect on idelalisib exposure.. Patients with Hepatic ImpairmentThe mean AUC increased up to 1.7-fold in patients with hepatic impairment (defined as ALT or AST or bilirubin values >= ULN) compared to patients with normal hepatic function. There is limited information on idelalisib exposure in patients with baseline AST or ALT 2.5 ULN or bilirubin 1.5 ULN [see Specific Populations (8.6)]. Drug Interaction Studies. Effect of Other Drugs on IdelalisibThe coadministration of rifampin (strong CYP3A inducer and P-gp inducer) to healthy subjects decreased the mean idelalisib AUC by 75% and the mean Cmax by 58% [see Drug Interactions (7.1)]. The coadministration of ketoconazole (strong CYP3A inhibitor and P-gp inhibitor) to healthy subjects increased the mean idelalisib AUC by 1.8-fold. No changes in the mean Cmax were observed [see Drug Interactions (7.1)]. In vitro studies suggest that idelalisib inhibits CYP2C8, CYP2C19, and UGT1A1 and induces CYP2B6.. Effect of Idelalisib on Other DrugsThe mean Cmax of midazolam increased by 2.4-fold and the mean AUC of midazolam increased by 5.4-fold when midazolam (sensitive CYP3A substrate) was coadministered with Zydelig [see Drug Interactions (7.2)]. No changes in exposure to rosuvastatin (OATP1B1 and OATP1B3 substrate) or digoxin (P-glycoprotein substrate) were observed when coadministered with Zydelig.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Relapsed Chronic Lymphocytic Leukemia. Study 312-0116Zydelig was evaluated in randomized, double-blind, placebo-controlled study GS-US-312-0116 (referred to as 312-0116) (NCT01539512) in 220 patients 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 >= neutropenia or Grade >= thrombocytopenia resulting from myelotoxic effects of prior therapy with cytotoxic agents. Patients were randomized 1:1 to receive doses of rituximab (first dose at 375 mg/m2, subsequent doses at 500 mg/m2 every weeks for infusions and every weeks for an additional infusions) in combination with either an placebo taken orally twice daily or with Zydelig 150 mg taken orally twice daily until disease progression or unacceptable toxicity.The median age was 71 years (range 47, 92) with 78% over 65, 66% were male, and 90% were White. The median time since diagnosis was 8.5 years. The median number of prior therapies was 3. Nearly all (96%) patients had received prior anti-CD20 monoclonal antibodies. The most common (>15%) prior regimens were: bendamustine rituximab (BR) (98 patients, 45%), fludarabine cyclophosphamide rituximab (75 patients, 34%), single-agent rituximab (67 patients, 31%), fludarabine rituximab (37 patients, 17%), and chlorambucil (36 patients, 16%). The median CIRS (Cumulative Illness Rating Scale) score was (range 0-17), and 85% of patients had score of >6. Median Karnofsky score was 80. Median estimated Creatinine Clearance (eCLcr) was 63.6 mL/min, with 41% of patients having an eCLcr of <60 mL/min. At screening, 19.5% of patients had platelet count of <50 109/L, and 13.2% had an absolute neutrophil count (ANC) of <1 109/L.The efficacy of Zydelig was based on 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 second interim analysis continued to show statistically significant improvement for Zydelig R compared to placebo R for the major efficacy outcome measure of PFS (HR: 0.18, 95% CI [0.10, 0.32], <0.0001).At the final analysis, with median follow-up of 8.3 months for the Zydelig R group, and 5.6 months for the placebo R group, the median PFS for the Zydelig R group was 19.4 months (95% CI: 12.3, Not Reached) versus 6.5 months (95% CI: 4.0, 7.3) for the placebo R group (HR: 0.15, 95% CI [0.09, 0.24], < 0.0001).Updated efficacy results are shown in Table and the Kaplan-Meier curve for PFS is shown in Figure 1.Table Efficacy Results from Study 312-0116Zydelig RN 110Placebo RN 110PFS: progression-free survival; NR: not reached; ORR: overall response rate; PR: partial response; DOR: duration of responsePFSMedian (months) (95% CI)19.4 (12.3, NR)6.5 (4.0, 7.3)Hazard ratio (95% CI)0.15 (0.09, 0.24)P-value< 0.0001 The value for PFS was based on stratified log-rank test. ORRORR defined as the proportion of patients who achieved complete response (CR) or PR. All PRs achieved; none of the patients achieved CR. (All PRs)92 (83.6%)17 (15.5%)95% CI75.4, 90.09.3, 23.6Odds Ratio (95% CI)27.8 (13.4, 57.5)P-value<0.0001DOR Median (months) (95% CI)NR (12, NR)6.2 (2.8, 6.5)Figure Kaplan-Meier Plot of IRC-Assessed PFS for Study 312-0116. Figure 1. 14.2Relapsed Follicular B-cell non-Hodgkin Lymphoma. Study 101-09Zydelig was evaluated in single-arm, multicenter study 101-09 (NCT01282424) which included 72 patients with follicular B-cell non-Hodgkin lymphoma who had relapsed within months following rituximab and an alkylating agent and had received at least prior treatments. Patients received Zydelig 150 mg 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 median age was 62 years (range 33 to 84), 54% were male, and 90% were White. At enrollment, 92% of patients had baseline ECOG performance status of or 1. The median time since diagnosis was 4.7 years and the median number of prior treatments was (range 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.The efficacy of Zydelig was based on Independent Review Committee-assessed overall response rate (ORR). Efficacy results are summarized in Table 8.Table Overall Response Rate (ORR) and Duration of Response (DOR) in Patients with Relapsed Follicular LymphomaN=72CI confidence interval; CR complete response; PR partial responseORR39 (54%) 95% CI(42, 66%) CR6 (8%) PR33 (46%)MedianKaplan-Meier estimate DOR, months (range)median not evaluable (0.0+, 14.8+)The median time to response was 1.9 months (range 1.6-8.3).. 14.3Relapsed Small Lymphocytic Lymphoma. Study 101-09Zydelig was evaluated in single-arm, multicenter study 101-09 (NCT01282424) which included 26 patients with small lymphocytic lymphoma (SLL) who had relapsed within months following rituximab and an alkylating agent and had received at least prior treatments. Patients received Zydelig 150 mg 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 median age was 65 years (range 50 to 87), 73% were male, and 81% were White. At enrollment, 96% of patients had baseline ECOG performance status of or 1. The median time since diagnosis was 6.7 years and the median number of prior treatments was (range 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.The efficacy was based on Independent Review Committee-assessed overall response rate (ORR). Efficacy results are summarized in Table 9.Table Overall Response Rate (ORR) and Duration of Response (DOR) in Patients with Relapsed Small Lymphocytic LymphomaN=26CI confidence interval; CR complete response; PR partial responseORR15 (58%) 95% CI(37, 77%) CR0 PR15 (58%)MedianKaplan-Meier estimate DOR, months (range)11.9 (0.0+, 14.7+)The median time to response was 1.9 months (range 1.6-8.3).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 LeukemiaThe 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 [see Clinical Studies (14.1)] and one randomized, open-label trial in 259 patients with relapsed CLL (Study 312-0119).. Zydelig with Rituximab (Study 312-0116)Patients with relapsed CLL received up to doses of rituximab (R) with or without Zydelig 150 mg twice daily. The median duration of exposure to Zydelig was 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 and Table summarize common adverse reactions and laboratory abnormalities reported for Zydelig R and placebo R arms.Table Adverse Reactions Reported in >=5% of Patients with CLL and Occurred at >=2% Higher Incidence in Patients Receiving Zydelig in Study 312-0116Zydelig RN=110 (%)Placebo RN=108 (%)Adverse ReactionAny GradeGrade >=3Any GradeGrade >=3General disorders and administration site conditions pyrexia44 (40)3 (3)20 (19)1 (1) chills27 (25)2 (2)17 (16)0 pain8 (7)01 (1)0Gastrointestinal disorders diarrhea Diarrhea includes the following preferred terms: diarrhea, colitis. 35 (32) 12 (11)20 (19)0 nausea30 (27)1 (1)25 (23)0 abdominal pain Abdominal pain includes the following preferred terms: abdominal pain, abdominal pain upper, abdominal pain lower. 20 (18)1 (1)17 (16)2 (2) vomiting 17 (15)09 (8)0 gastroesophageal reflux disease11 (10)1 (1)00 stomatitis7 (6)2 (2)1 (1)0Respiratory, thoracic, and mediastinal disorders pneumonia Pneumonia includes the terms: pneumonia, pneumonitis, lung infection, lung infiltration, pneumocystis jiroveci pneumonia, pneumonia legionella, lung infection pseudomonal, pneumonia fungal, respiratory tract infection, lower respiratory tract infection, and lower respiratory tract infection bacterial. 33 (30)23 (21)20 (19)14 (13)Skin and subcutaneous tissue disorders rash Rash includes the following preferred terms: dermatitis exfoliative, drug eruption, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, rash morbilliform, and exfoliative rash. 27 (25)4 (4)7 (6)1 (1)Metabolism and Nutrition Disorders decreased appetite18 (16)2 (2)12 (11)2 (2) dehydration7 (6)3 (3)00Infections and infestations sepsis Sepsis includes the terms: sepsis, septic shock, neutropenic sepsis, and sepsis syndrome 10 (9)10 (9)4 (4)4 (4) sinusitis (8)06 (6)0 urinary tract infection9 (8)1 (1)4 (4)2 (2) bronchitis (7)1 (1)5 (5)1 (1) oral herpes6 (5)1 (1)3 (3)0Psychiatric disorders insomnia10 (9)07 (6)0Musculoskeletal and connective tissue disorders arthralgia9 (8)1 (1)4 (4)0Nervous system disorders lethargy6 (5)02 (2)0Table Hematologic and Hepatic Laboratory Abnormalities Reported in >=10% of Patients with CLL and Occurred at >=5% Higher Incidence in Patients Receiving Zydelig in Study 312-0116Zydelig RN=110 (%)Placebo RN=108 (%)Laboratory ParameterAny GradeGrade 3-4Any GradeGrade 3-4Hematology abnormalities neutropenia71 (65)46 (42)61 (56)33 (31) leukopenia34 (31)9 (8)25 (23)9 (8) lymphocytopenia23 (21)11 (10)13 (12)4 (4)Serum chemistry abnormalities ALT increased43 (39)10 (9)13 (12)1 (1) AST increased31 (28)6 (5)16 (15)0After closure of Study 312-0116, 71 patients continued treatment with Zydelig on an extension study (Study 312-0117). The median duration of exposure was 18 months. Serious adverse reactions occurred in 48 (68%) patients. The most frequent serious adverse reactions reported were pneumonia (30%), diarrhea (15%), and pyrexia (11%).The most frequent adverse reactions were pneumonia (51%), pyrexia (46%), and cough (45%). The most frequent Grade or greater adverse reactions were pneumonia (30%), diarrhea (15%), and sepsis (10%).. Zydelig with Ofatumumab (Study 312-0119)In Study 312-0119, 259 patients with relapsed CLL received up to 12 doses of ofatumumab with or without Zydelig 150 mg orally twice daily. The median duration of exposure to Zydelig was 13.9 months.Serious adverse reactions were reported in 133 (77%) patients treated with Zydelig ofatumumab. The most frequent serious adverse reactions reported were pneumonia (14%), pyrexia (13%), and diarrhea (12%).Adverse reactions that led to discontinuation of Zydelig occurred in 71 (41%) patients.One hundred and ten (64%) patients had dose interruptions and 42 (24%) patients had dose reductions due to adverse reactions or laboratory abnormalities. The most common reasons for dose discontinuations, reductions, or interruptions were diarrhea and colitis.The most common adverse reactions were diarrhea (55%), pyrexia (38%), nausea (34%), and fatigue (34%).. Zydelig with Bendamustine and Rituximab (Study 312-0115)In Study 312-0115, patients with relapsed CLL received up to cycles of bendamustine and rituximab (BR) with or without Zydelig 150 mg orally twice daily. The median duration of exposure to Zydelig was 18.2 months.Serious adverse reactions were reported in 147 (71%) patients treated with Zydelig BR. The most frequent serious adverse reactions reported for patients treated with Zydelig BR were febrile neutropenia (21%), pneumonia (17%), pyrexia (12%), and diarrhea (6%).Adverse reactions that led to discontinuation of Zydelig occurred in 68 (33%) patients. The most common adverse reactions that led to treatment discontinuations were pneumonia, diarrhea, and pyrexia.One hundred twenty-two (59%) patients treated with Zydelig BR had dose interruptions and 34 (16%) patients had dose reductions due to adverse reactions. The most common reasons for dose interruptions or reductions were increased ALT and diarrhea.The most common adverse reactions were neutropenia (64%), pyrexia (43%), and diarrhea (41%).. Summary of Clinical Trials in Indolent Non-Hodgkin LymphomaThe safety data reflect exposure to Zydelig from three open-label clinical trials (Studies 101-09, 101-02, and 101-10 in 146 patients with indolent non-Hodgkin lymphoma (iNHL) treated with Zydelig 150 mg orally twice daily [see Clinical Studies (14.2, 14.3)]. 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 provides the adverse reactions occurring in at least 10% of patients receiving Zydelig monotherapy and Table provides the hematologic and hepatic laboratory abnormalities.Table Adverse Reactions Reported in >= 10% of Patients with Indolent NHL Treated with ZydeligZydelig MonotherapyN=146 (%)Adverse ReactionAny GradeGrade >=3Gastrointestinal disorders diarrhea Diarrhea includes the following preferred terms: diarrhea, colitis, enterocolitis, and gastrointestinal inflammation. 68 (47)20 (14) nausea42 (29)2 (1) abdominal pain Abdominal pain includes the following preferred terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. 38 (26)3 (2) vomiting22 (15)2 (1)General disorders and administration site conditions fatigue44 (30)2 (1) pyrexia41 (28)3 (2) asthenia17 (12)3 (2) peripheral edema15 (10)3 (2)Respiratory, thoracic, and mediastinal disorders cough42 (29)1 (1) pneumonia 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. 37 (25)23 (16) dyspnea25 (17)6 (4)Skin and subcutaneous disorders rash Rash includes the following preferred terms: dermatitis exfoliative, rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, and exfoliative rash. 31 (21)4 (3) night sweats18 (12)0Metabolism and nutrition disorders decreased appetite24 (16)1 (1)Infections and infestations upper respiratory tract infection18 (12)0Psychiatric disorders insomnia17 (12)0Nervous system disorders headache16 (11)1 (1)Table Hematologic and Hepatic Laboratory Abnormalities in Patients with Indolent non-Hodgkin Lymphoma Treated with ZydeligZydelig MonotherapyN=146 (%)Laboratory AbnormalityAny GradeGrade 3Grade 4Grades were obtained per CTCAE version 4.03.Serum chemistry abnormalities ALT increased73 (50)20 (14)7 (5) AST increased60 (41)12 (8)6 (4)Hematology abnormalities neutrophils decreased78 (53)20 (14)16 (11) hemoglobin decreased41 (28)3 (2)0 platelets decreased38 (26)4 (3)5 (3). Summary of Discontinued Clinical Trials in First-Line CLL and Early Line iNHLSafety data described below reflect exposure to Zydelig in three randomized, double-blind clinical trials (Studies 312-0123, 313-0124, and 313-0125) in patients with CLL and iNHL.In Study 312-0123 (NCT01980888), 311 patients with previously untreated CLL received up to cycles of BR with or without Zydelig 150 mg twice daily.In Study 313-0124 (NCT01732913), 295 patients with previously treated iNHL received doses of with or without Zydelig 150 mg twice daily. Patients had median of one prior therapy.In Study 313-0125 (NCT01732926), 475 patients with previously treated iNHL received up to cycles of BR with or without Zydelig 150 mg twice daily. Patients had median of two prior therapies.These three studies were terminated early due to higher incidence of fatal and/or serious adverse reactions observed in patients treated with Zydelig in combination with 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended dosage: 150 mg orally twice daily. (2.1). 2.1 Recommended Dosage. The recommended dosage of Zydelig is 150 mg administered orally twice daily with or without food until disease progression or unacceptable toxicity. The optimal and safe dosing regimen for patients who receive treatment longer than several months is unknown.Swallow tablets whole.If planned dose of Zydelig is missed by less than hours, take the missed dose as soon as possible and take the next dose as usual. If dose of Zydelig is missed by more than hours, skip the missed dose and take the next dose at the usual time.. 2.2 Dose Modifications for Adverse Reactions. Table presents the dosage modification for specific adverse reactions.For other severe or life-threatening adverse reactions, withhold Zydelig until resolution. If resuming Zydelig after interruption for other severe or life-threatening toxicities, reduce the dosage to 100 mg orally twice daily. Permanently discontinue Zydelig for recurrence of other severe or life-threatening Zydelig-related toxicity upon rechallenge.Table Dosage Modifications for Adverse ReactionsAbbreviations: ANC: absolute neutrophil count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; ULN, upper limit of normal; CMV, cytomegalovirus; DRESS, drug reaction with eosinophilia and systemic symptoms; PCR: polymerase chain reaction; PJP: Pneumocystis jirovecii pneumonia; SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysisALT/AST>3-5 ULN>5-20 ULN>20 ULN[see Warnings and Precautions (5.1)]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[see Warnings and Precautions (5.1)]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.DiarrheaModerate diarrhea: increase of 4-6 stools per day over baseline; severe diarrhea: increase of >=7 stools per day over baseline. Moderate diarrheaSevere diarrhea or hospitalizationLife-threatening diarrhea[see Warnings and Precautions (5.2)]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.PneumonitisAny symptomatic pneumonitis[see Warnings and Precautions (5.3)]Discontinue Zydelig in patients with any severity of symptomatic pneumonitis.InfectionsGrade or higher sepsis or pneumonia[see Warnings and Precautions (5.4)]Interrupt Zydelig until infection has resolved.Evidence of CMV infection or viremiaInterrupt 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 infectionInterrupt Zydelig in patients with suspected PJP infection of any grade.Permanently discontinue Zydelig if PJP infection is confirmed.Intestinal PerforationEvidence of intestinal perforation[see Warnings and Precautions (5.5)]Permanently discontinue Zydelig in patients who experience intestinal perforation.Severe Cutaneous ReactionsSuspected/Confirmed SJS, TEN, or DRESS[see Warnings and Precautions (5.6)]Interrupt Zydelig in patients with suspected SJS, TEN, or DRESS until the etiology of the reaction has been determined.Permanently discontinue Zydelig in patients with confirmed SJS, TEN, or DRESS.Hypersensitivity ReactionsEvidence of hypersensitivity reactions[see Warnings and Precautions (5.7)]Permanently discontinue Zydelig in patients who develop serious hypersensitivity reactions.NeutropeniaANC 1.0 to <1.5 Gi/LANC 0.5 to <1.0 Gi/LANC <0.5 Gi/L[see Warnings and Precautions (5.8)]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.ThrombocytopeniaPlatelets 50 to <75 Gi/LPlatelets 25 to <50 Gi/LPlatelets <25 Gi/L[see Adverse Reactions (6.1)]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.No dosage modification is recommended for lymphocytosis, which has been observed in some patients taking Zydelig. This observed lymphocytosis is pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical findings.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. HepatotoxicityAdvise 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 ColitisAdvise patients that Zydelig may cause severe diarrhea or colitis and to notify their healthcare provider immediately if the number of bowel movements in day increases by six or more [see Warnings and Precautions (5.2)]. PneumonitisAdvise 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)]. InfectionsAdvise patients that Zydelig can cause serious infections that may be fatal. Advise patients to immediately report symptoms of infection (e.g. pyrexia) [see Warnings and Precautions (5.4)].. Intestinal PerforationAdvise patients of the possibility for intestinal perforation and to notify their healthcare provider immediately if they experience severe abdominal pain [see Warnings and Precautions (5.5)]. Severe Cutaneous ReactionsAdvise patients that Zydelig may cause severe cutaneous reactions and to notify their healthcare provider immediately if they develop severe skin reaction [see Warnings and Precautions (5.6)]. Hypersensitivity ReactionsAdvise patients that anaphylaxis can occur during treatment with Zydelig and to notify their healthcare provider immediately if they experience hypersensitivity reaction, including anaphylaxis [see Warnings and Precautions (5.7)]. NeutropeniaAdvise patients of the need for periodic monitoring of blood counts. Advise patients to notify their healthcare provider immediately if they develop fever or any signs of infection [see Warnings and Precautions (5.8)]. Embryo-Fetal ToxicityAdvise pregnant women of the potential risk to fetus. Advise females of reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.9), Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception during treatment with Zydelig and for month after the last dose [see Use in Specific Populations (8.3)].Advise males with female partners of reproductive potential to use effective contraception during treatment with Zydelig and for months after receiving the last dose [see Use in Specific Populations (8.3)].. LactationAdvise women not to breastfeed during treatment with Zydelig and for at least month after the last dose [see Use in Specific Populations (8.2)].. Instructions for Taking ZydeligAdvise 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 dose of Zydelig is missed by less than hours, to take the missed dose right away and take the next dose as usual. If dose of Zydelig is missed by more than hours, advise patients to wait and take the next dose at the usual time [see Dosage and Administration (2.1)].

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics. Idelalisib exposure increased in less than dose-proportional manner over dose range of 50 mg to 350 mg twice daily (0.3 to 2.3 times the approved recommended dosage).Following 150 mg twice daily administration of idelalisib, average (% coefficient of variation) maximum concentrations (Cmax) and area under the curve (AUC) at steady-state were 1861 (43%) ng/mL and 10598 (41%) ngh/mL for idelalisib.. AbsorptionThe median time to peak concentration (Tmax) was observed at 1.5 hours.. Food EffectThe administration of single dose of Zydelig with high-fat meal (900 calories: 525 calories fat, 250 calories carbohydrates, and 125 calories protein) increased idelalisib AUC 1.4-fold relative to fasting conditions.. DistributionProtein binding of idelalisib is >= 84% with no concentration dependence.The mean blood-to-plasma ratio was 0.7.The apparent central volume of distribution at steady state is 23 (%CV ~85%). Idelalisib is substrate of P-glycoprotein (P-gp) and BCRP in vitro.. EliminationThe population apparent systemic clearance at steady-state is 14.9 L/hr (%CV 38%). The population terminal elimination half-life of idelalisib is 8.2 hours.. MetabolismIdelalisib is metabolized via aldehyde oxidase and CYP3A with additional minor metabolism by UGT1A4.. ExcretionFollowing single 150 mg dose of radiolabeled idelalisib, 78% of the radioactivity was excreted in feces and 14% was excreted in the urine. Idelalisib is not substrate of OATP1B1, OATP1B3, OAT1, OAT3, or OCT2.. Specific PopulationsAge (18 to 91 years), sex, race (White, and non-Whites), renal impairment (creatinine clearance >= 15 mL/min) and weight (38 to 148 kg) had no effect on idelalisib exposure.. Patients with Hepatic ImpairmentThe mean AUC increased up to 1.7-fold in patients with hepatic impairment (defined as ALT or AST or bilirubin values >= ULN) compared to patients with normal hepatic function. There is limited information on idelalisib exposure in patients with baseline AST or ALT 2.5 ULN or bilirubin 1.5 ULN [see Specific Populations (8.6)]. Drug Interaction Studies. Effect of Other Drugs on IdelalisibThe coadministration of rifampin (strong CYP3A inducer and P-gp inducer) to healthy subjects decreased the mean idelalisib AUC by 75% and the mean Cmax by 58% [see Drug Interactions (7.1)]. The coadministration of ketoconazole (strong CYP3A inhibitor and P-gp inhibitor) to healthy subjects increased the mean idelalisib AUC by 1.8-fold. No changes in the mean Cmax were observed [see Drug Interactions (7.1)]. In vitro studies suggest that idelalisib inhibits CYP2C8, CYP2C19, and UGT1A1 and induces CYP2B6.. Effect of Idelalisib on Other DrugsThe mean Cmax of midazolam increased by 2.4-fold and the mean AUC of midazolam increased by 5.4-fold when midazolam (sensitive CYP3A substrate) was coadministered with Zydelig [see Drug Interactions (7.2)]. No changes in exposure to rosuvastatin (OATP1B1 and OATP1B3 substrate) or digoxin (P-glycoprotein substrate) were observed when coadministered with Zydelig.