Zydelig

Before taking idelalisib,

• tell your doctor and pharmacist if you are allergic to idelalisib, any other medications, or any of the ingredients in idelalisib tablets. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: carbamazepine (Carbatrol, Epitol, Equetro, others); clarithromycin (Biaxin, in PrevPac); itraconazole (Onmel, Sporanox); ketoconazole (Nizoral); medications used to treat human immunodeficiency virus (HIV) such as efavirenz (Sustiva, in Atripla), indinavir (Crixivan), nelfinavir (Viracept), nevirapine (Viramune), ritonavir (Norvir, in Kaletra, in Technivie); midazolam; nefazodone; phenobarbital; phenytoin (Dilantin, Phenytek); pioglitazone (Actos, in Actoplus Met, in Duetact, in Oseni); rifabutin (Mycobutin); and rifampin (Rifadin, Rimactane, in Rifamate, in Rifater). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with idelalisib, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor and pharmacist what herbal products you are taking, especially St. John's wort. You should not take St. John's wort during your treatment with idelalisib.
• tell your doctor if you are pregnant or plan to become pregnant. You should not become pregnant during your treatment with idelalisib. You should use birth control to prevent pregnancy during your treatment with idelalisib and for up to 1 month after your treatment. If you become pregnant while taking idelalisib, call your doctor immediately. Idelalisib may harm the fetus.
• tell your doctor if you are breastfeeding. You should not breastfeed while you are taking idelalisib.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The recommended starting dose of Zydelig (idelalisib) is 150 mg twice daily.

Your doctor may adjust your dose if you experience certain adverse effects.

• Importance of instructing patients to read the manufacturer's patient information before starting idelalisib therapy and each time their prescription is refilled.1

• Importance of advising patients to take idelalisib exactly as prescribed and of not altering the dosage or discontinuing therapy unless advised to do so by their clinician.1 Importance of advising patients to swallow idelalisib tablets whole.1

• If a dose is missed, importance of advising patients to take it as soon as they remember unless the dose was missed by >6 hours, in which case they should not take the missed dose.1

• Risk of hepatotoxicity; importance of regular liver function test monitoring.1 Importance of advising patients to immediately report possible symptoms of hepatotoxicity (e.g., abdominal pain [especially right upper quadrant pain], jaundice, dark urine, bruising, bleeding diathesis) to their clinician.1

• Risk of severe diarrhea or colitis.1 Importance of immediately informing clinician if frequency of bowel movements increases by ≥6 within a day.1

• Risk of intestinal perforation.1 Importance of immediately informing clinician if new or worsening abdominal pain, chills, fever, nausea, or vomiting occurs.1

• Risk of pneumonitis.1 Importance of immediately informing clinician if new or worsening respiratory symptoms (e.g., cough, dyspnea, wheezing) occur.1

• Risk of anaphylaxis or severe dermatologic reactions.1 Importance of immediately informing clinician if anaphylaxis or severe dermatologic reactions occur.1

• Risk of neutropenia.1 Importance of periodically monitoring CBC during idelalisib therapy.1 Importance of immediately informing clinician if signs of infection (e.g., fever) occur.1

• Risk of fetal harm.1 Necessity of advising women of childbearing potential to avoid pregnancy and to consider using effective contraceptive methods while receiving idelalisib and for ≥1 month following discontinuance of therapy.1 Importance of women informing clinicians immediately if they become pregnant during therapy or think they may be pregnant.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1

• Importance of advising women to avoid breast-feeding while receiving idelalisib therapy.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., hepatic impairment).1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

• If you have an allergy to Zydelig or any part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are taking any of these drugs: Carbamazepine, phenytoin, rifampin, or St. John's wort.
• If you are taking any drugs that can raise the chance of liver problems. There are many drugs that can do this. Ask your doctor or pharmacist if you are not sure.
• If you are taking any drugs that can cause loose stools (diarrhea). There are many drugs that can do this. Ask your doctor or pharmacist if you are not sure.
• If you are breast-feeding. Do not breast-feed while you take Zydelig.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Zydelig with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Loose stools (diarrhea).
• Headache.
• Heartburn.
• Joint pain.
• Not hungry.
• Feeling tired or weak.
• Not able to sleep.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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)]
• Infections [see Warnings and Precautions (5.4)]
• Intestinal Perforation [see Warnings and Precautions (5.5)]
• Severe Cutaneous Reactions [see Warnings and Precautions (5.6)]
• Anaphylaxis [see Warnings and Precautions (5.7)]
• Neutropenia [see Warnings and Precautions (5.8)]

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 8 months.

Serious adverse reactions were reported in 65 (59%) subjects treated with Zydelig + rituximab. The most frequent serious adverse reactions reported for subjects treated with Zydelig 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%) subjects. The most common adverse reactions that led to treatment discontinuations were hepatotoxicity and diarrhea/colitis.

Forty-two subjects (38%) had dose interruptions and sixteen subjects (15%) had dose reductions due to adverse reactions or laboratory abnormalities. The most common reasons for dose interruptions or reductions were pneumonia, diarrhea or colitis, rash, and elevated transaminases.

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

After closure of Study 1, 71 patients continued treatment with Zydelig on an extension study. The median duration of exposure was 18 months. Serious adverse reactions occurred in 48 (68%) subjects. The most frequent serious adverse reactions reported were pneumonia (30%), diarrhea (15%), and pyrexia (11%).

The most frequent adverse reactions were pneumonia (51%), pyrexia (46%), and cough (45%). The most frequent Grade 3 or greater adverse reactions were pneumonia (30%), diarrhea (15%), and sepsis (10%).

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.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Zydelig. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Disorders

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)

Effects of Other Drugs on Zydelig

CYP3A Inducers

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

CYP3A Inhibitors

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

Effects of Zydelig on Other Drugs

CYP3A Substrates

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

Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.9)]

Risk Summary

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

Animal Data

In an embryo-fetal development study, pregnant rats were administered oral doses of idelalisib during the period of organogenesis at 25, 75, and 150 mg/kg/day. Embryo-fetal toxicities were observed at the mid- and high-doses that also resulted in maternal toxicity, based on reductions in maternal body weight gain. Adverse findings at idelalisib doses ≥ 75 mg/kg/day included decreased fetal weights, external malformations (short tail), and skeletal variations (delayed ossification and/or unossification of the skull, vertebrae, and sternebrae). Additional findings were observed at 150 mg/kg/day dose of idelalisib and included urogenital blood loss, complete resorption, increased post-implantation loss, and malformations (vertebral agenesis with anury, hydrocephaly, and microphthalmia/anophthalmia). The dose of 75 and 150 mg/kg/day of idelalisib in rats resulted in exposures (AUC) of approximately 12 and 30 times, respectively, the human exposure at the recommended dose of 150 mg twice daily.

Nursing Mothers

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

Pediatric Use

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

Geriatric Use

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

Females of Reproductive Potential

Contraception

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

Renal Impairment

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

Hepatic Impairment

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with idelalisib have not been conducted.

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

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

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

Animal Pharmacology and/or Toxicology

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

Relapsed Chronic Lymphocytic Leukemia

Zydelig was evaluated in a randomized, double-blind, placebo-controlled study (Study 1) in 220 subjects with relapsed CLL who required treatment and were unable to tolerate standard chemoimmunotherapy due to coexisting medical conditions, reduced renal function as measured by creatinine clearance <60 mL/min, or NCI CTCAE Grade ≥3 neutropenia or Grade ≥3 thrombocytopenia resulting from myelotoxic effects of prior therapy with cytotoxic agents. Subjects were randomized 1:1 to receive 8 doses of rituximab (first dose at 375 mg/m2, subsequent doses at 500 mg/m2 every 2 weeks for 4 infusions and every 4 weeks for an additional 4 infusions) in combination with either an oral placebo twice daily or with Zydelig 150 mg taken twice daily until disease progression or unacceptable toxicity.

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

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

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

Relapsed Follicular B-cell non-Hodgkin Lymphoma

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

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

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

Relapsed Small Lymphocytic Lymphoma

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

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

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

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

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

• Hepatotoxicity

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

• Severe Diarrhea or Colitis

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

• Pneumonitis

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

• Infections

Advise 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 Perforation

Advise patients of the possibility for intestinal perforation and to notify their healthcare provider immediately if they experience severe abdominal pain [see Warnings and Precautions (5.5)].

• Severe Cutaneous Reactions

Advise patients that Zydelig may cause severe cutaneous reactions and to notify their healthcare provider immediately if they develop a severe skin reaction [see Warnings and Precautions (5.6)].

• Anaphylaxis

Advise patients that anaphylaxis can occur during treatment with Zydelig and to notify their healthcare provider immediately if they experience symptoms of anaphylaxis [see Warnings and Precautions (5.7)].

• Neutropenia

Advise patients of the need for periodic monitoring of blood counts. Advise patients to notify their healthcare provider immediately if they develop a fever or any signs of infection [see Warnings and Precautions (5.8)].

• Pregnancy and Nursing

Advise women of the potential hazard to the fetus and to avoid pregnancy during treatment with Zydelig. If contraceptive methods are being considered, advise to use adequate contraception during therapy and for at least one month after completing therapy. Also advise patients not to breastfeed while taking Zydelig [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1, 8.3, and 8.6)].

• Instructions for Taking Zydelig

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

Manufactured and distributed by:

Gilead Sciences, Inc.

Foster City, CA 94404

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

©2016 Gilead Sciences, Inc. All rights reserved.

205858-GS-001-PI

Take the missed dose as soon as you remember. If you are more than 6 hours late, skip the missed dose. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.