Drug Safety-related Labeling Changes (SrLC) Database
ANDA | Abbreviated New Drug Application |
BLA | Biologics License Application |
CDER | Center for Drug Evaluation and Research |
MG | Medication Guide |
NDA | New Drug Application |
PCI | Patient Counseling Information |
PI | Patient Information |
PLR | Physician Labeling Rule |
PLLR | Pregnancy and Lactation Labeling Rule |
Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
BW | Box Warning |
WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
ZYDELIG (NDA-205858)
(IDELALISIB)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
02/18/2022 (SUPPL-16)
Boxed Warning
Additions and/or revisions underlined:
Fatal and/or serious hepatotoxicity occurred in 16% (removed ‘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 (removed ‘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 (removed ‘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)].
5 Warnings and Precautions
Added missing cross references to “Adverse Reactions (6.1)” to Sections 5.3 Pneumonitis, 5.6 Severe Cutaneous Reactions, and 5.8 Neutropenia.
6 Adverse Reactions
6.1 Clinical Trials ExperienceAdditions and/or revisions underlined:
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.
The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to Zydelig at a dosage of 150 mg twice daily in 110 patients administered in combination with rituximab in Study 312-0116, and in combination with other drugs in 380 patients. Among 490 patients who received Zydelig, 74% were exposed for 6 months or longer and 50% were exposed for one year or longer. In this pooled safety population, the most common (> 30%) adverse reactions were diarrhea, pneumonia, pyrexia, fatigue, rash, cough, and nausea. Common laboratory abnormalities were neutropenia, ALT elevations and AST elevations.
Summary of Clinical Trials in Chronic Lymphocytic Leukemia
Zydelig with Rituximab (Study 312-0116)
Patients with relapsed CLL received up to 8 doses of rituximab (R) with (n=110) or without Zydelig (n=108)150 mg twice daily. The median duration of exposure to Zydelig was 8 months.
Following Table 3: Hematologic and Hepatic Laboratory Abnormalities Reported in greater than or equal to 10% of Patients with CLL and Occurred at greater than or equal to 5% Higher Incidence in Patients Receiving Zydelig in Study 312-0116 Patients Receiving Zydelig in Study 312-0116:
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. Zydelig in combination with ofatumumab is not indicated for the treatment of relapsed CLL. The median duration of exposure to Zydelig was 13.9 months.
Zydelig with Bendamustine and Rituximab (Study 312-0115)
In Study 312-0115, patients with relapsed CLL received up to 6 cycles of bendamustine and rituximab (BR) with or without Zydelig 150 mg orally twice daily. Zydelig in combination with bendamustine and rituximab is not indicated for the treatment of relapsed CLL. The median duration of exposure to Zydelig was 18.2 months.
Summary of Clinical Trials in Indolent Non-Hodgkin Lymphoma
The safety data reflect exposure to Zydelig from three open-label clinical trials (Studies 101-09, 101-02, and 101-10 in 146 patients with indolent non-Hodgkin lymphoma (iNHL) treated with Zydelig 150 mg orally twice daily. Zydelig is not indicated for the treatment of iNHL. 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%).
The most common adverse reactions were neutropenia (53%), ALT increased (50%), diarrhea (47%), AST increased (41%), fatigue (30%), nausea and cough (29% each), anemia and pyrexia (28% each), abdominal pain and thrombocytopenia (26% each), and pneumonia (25%).
Summary of Discontinued Clinical Trials in Indolent Non-Hodgkin Lymphoma and First- Line CLL Zydelig is not indicated for patients with indolent non-Hodgkin lymphoma or previously untreated CLL either as monotherapy or in combination with rituximab or BR. Safety 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 6 cycles of BR with or without Zydelig 150 mg twice daily.
In Study 313-0124 (NCT01732913), 295 patients with previously treated iNHL [FL 66%, marginal zone lymphoma (MZL) 19%, SLL 9%, lymphoplasmacytic lymphoma (LPL)/Waldenstrom macroglobulinemia (WM) 6%] received 8 doses of R with or without Zydelig 150 mg twice daily. Patients had a median of one prior therapy.
In Study 313-0125 (NCT01732926), 475 patients with previously treated iNHL (FL 63%, MZL 15%, SLL 11%, LPL/WM 11%) received up to 6 cycles of BR with or without Zydelig 150 mg twice daily …
8 Use in Specific Populations
8.5 Geriatric UseAdditions and/or revisions underlined:
Of the 490 patients with relapsed CLL who were treated with Zydelig in combination trials, 271 (55%) were 65 years of age and older. When comparing patients 65 years of age or older to younger patients with CLL, older patients had a 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%).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEWhat is Zydelig?
Newly added information:
Zydelig should not be used as the first medicine to treat anyone, including people with CLL, small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and other slow growing (indolent) non-Hodgkin lymphomas.
Zydelig should not be used in combination with bendamustine and rituximab, or in combination with rituximab to treat people with FL, SLL, and other indolent non-Hodgkin lymphomas.
It is not known if Zydelig is safe and effective in children (‘less than 18 years of age’ removed).
Additions and/or revisions underlined:
What are the possible side effects of Zydelig?
Zydelig can cause serious side effects, including:
Serious allergic reactions, including a severe reaction known as anaphylaxis. Tell your healthcare provider or get medical help right away if you have signs or symptoms of a serious allergic reaction during treatment with Zydelig, including:
swelling of the face, lips, or tongue
rash or hives
trouble breathing or swallowing
cough
feeling dizzy or faint
a fast heartbeat
10/19/2020 (SUPPL-14)
4 Contraindications
(Additions underlined)
Zydelig is contraindicated in patients with a history of serious hypersensitivity reactions to idelalisib, including anaphylaxis, or patients with a history of toxic epidermal necrolysis with any drug [see Warnings and Precautions (5.6, 5.7)].
5 Warnings and Precautions
5.6 Severe Cutaneous Reactions(Additions underlined)
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 a 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 greater than or equal to3) 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)].
(Additions underlined)
Serious hypersensitivity reactions, including anaphylaxis, have been reported in patients on Zydelig. Zydelig is contraindicated in patients with a 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.
(Additions underlined)
Grade 3 or 4 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 2 weeks for the first 6 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)].
6 Adverse Reactions
6.2 Postmarketing Experience(Additions underlined)
…
Skin and Subcutaneous Disorders - Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE(Additions underlined)
…
Do not take Zydelig if you:
· have had a serious allergic reaction to idelalisib.
· have had a severe skin reaction called toxic epidermal necrolysis (TEN) to any drug.
…
(Additions underlined)
…
Advise males with female partners of reproductive potential to use effective contraception during treatment with Zydelig and for 3 months after receiving the last dose [see Use in Specific Populations (8.3)].
…
10/10/2018 (SUPPL-13)
7 Drug Interactions
7.1 Effects of Other Drugs on Zydelig(additions underlined)
Table 6 lists the potential effects of the coadministration of strong CYP3A modulators on Zydelig.
Table 6 Drug Interactions with Zydelig that affect Idelalisib Concentrations
(please refer to label to view Table 6)
01/26/2018 (SUPPL-9)
Boxed Warning
(Additions and/or revisions are underlined)
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…
Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 20% of Zydelig-treated patients…
Fatal and/or serious infections occurred in 21% to 48% of Zydelig-treated patients…
5 Warnings and Precautions
5.1 Hepatotoxicity(Additions and/or revisions are underlined)
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…
(Additions and/or revisions are underlined)
Severe diarrhea or colitis (Grade 3 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…
(Additions and/or revisions are underlined)
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 a radiologic exam, or a 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.
(Additions and/or revisions are underlined)
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. 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 3 or higher infection.
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…
(Additions and/or revisions are underlined)
Treatment-emergent Grade 3 or 4 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...
(Additions and/or revisions are underlined)
Based on findings in animals and its mechanism of action, Zydelig may cause fetal harm when administered to a 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 a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose.
6 Adverse Reactions
6.1 Clinical Trial Experience(Additions and/or revisions are underlined)
Summary of Clinical Trials in Chronic Lymphocytic Leukemia
The safety data reflect exposure to Zydelig from two randomized, double-blind clinical trials (Studies 312-0116 and 312-0115) in 634 patients with relapsed CLL and one randomized, open-label trial in 259 patients with relapsed CLL (Study 312-0119).
Zydelig with Rituximab (Study 312-0116; NCT01539512)
Patients with relapsed CLL received up to 8 doses of rituximab (R) with or without Zydelig 150 mg twice daily. The median duration of exposure to Zydelig was 8 months.
Serious adverse reactions were reported in 65 (59%) patients treated with Zydelig + R The most frequent serious adverse reactions reported for patients treated with Zydelig + R were pneumonia (23%), diarrhea (10%), pyrexia (9%), sepsis (8%), and febrile neutropenia (5%). Adverse reactions that led to discontinuation of Zydelig occurred in 19 (17%) patients…
Forty-two (38%) patients had dose interruptions and sixteen (15%) patients had dose reductions due to adverse reactions or laboratory abnormalities…
Table 2 and Table 3 summarize common adverse reactions and laboratory abnormalities reported for Zydelig + R and placebo + R arms.
Table 2 Adverse Reactions Reported in Greater than or Equal to 5% of Patients with CLL and Occurred at Greater than or Equal to 2% Higher Incidence in Patients Receiving Zydelig in Study 312-0116
Table 3 Hematologic and Hepatic Laboratory Abnormalities Reported in Greater than or Equal to 10% of Patients with CLL and Occurred at Greater than or Equal to 5% Higher Incidence in Patients Receiving Zydelig in Study 312-0116
After closure of Study 312-0116, 71 patients continued treatment with Zydelig on an extension study (Study 312-0117; NCT01539291). The median duration of exposure was 18 months. Serious adverse reactions occurred in 48 (68%) patients…
Zydelig with Ofatumumab (Study 312-0119; NCT01659021)
In Study 312-0119, 259 patients with relapsed CLL received up to 12 doses of ofatumumab with or without Zydelig 150 mg twice daily. The median duration of exposure to Zydelig was 13.9 months.
Serious adverse reactions were reported in 133 (77%) patients treated with Zydelig + ofatumumab. The most frequent serious adverse reactions reported were pneumonia (14%), pyrexia (13%), and diarrhea (12%).
Adverse reactions that led to discontinuation of Zydelig occurred in 71 (41%) patients. One hundred and ten (64%) patients had dose interruptions and 42 (24%) patients had dose reductions due to adverse reactions or laboratory abnormalities. The most common reasons for dose discontinuations, reductions, or interruptions were diarrhea and colitis. The most common adverse reactions were diarrhea (55%), pyrexia (38%), nausea (34%), and fatigue (34%).
Zydelig with Bendamustine and Rituximab (Study 312-0115; NCT01569295)
In Study 312-0115, patients with relapsed CLL received up to 6 cycles of bendamustine and rituximab (BR) with or without Zydelig 150 mg twice daily. The median duration of exposure to Zydelig was 18.2 months.
Serious adverse reactions were reported in 147 (71%) patients treated with Zydelig + BR. The most frequent serious adverse reactions reported for patients treated with Zydelig + BR were febrile neutropenia (21%), pneumonia (17%), pyrexia (12%), and diarrhea (6%).
Adverse reactions that led to discontinuation of Zydelig occurred in 68 (33%) patients. The most common adverse reactions that led to treatment discontinuations were pneumonia, diarrhea, and pyrexia.
One hundred twenty-two (59%) patients treated with Zydelig + BR had dose interruptions and 34 (16%) patients had dose reductions due to adverse reactions. The most common reasons for dose interruptions or reductions were increased ALT and diarrhea. The most common adverse reactions were neutropenia (64%), pyrexia (43%), and diarrhea (41%).
Summary of Clinical Trials in Indolent Non-Hodgkin Lymphoma
The safety data reflect exposure to Zydelig from three open-label clinical trials (Studies 101-09 (NCT01282424), 101-02 (NCT00710528), and 101-10 (NCT01306643) in 146patients with indolent non-Hodgkin lymphoma (iNHL) treated with Zydelig 150 mg twice daily. The median duration of exposure was 6.1 months (range 0.3 to 26.4 months).
Serious adverse reactions were reported in 73 (50%) patients…
Adverse reactions resulted in interruption or discontinuation for 78 (53%) patients…
Table 6 provides the adverse reactions occurring in at least 10% of patients receiving Zydelig monotherapy, and Table 7 provides the hematologic and hepatic laboratory abnormalities.
Table 6 Adverse Reactions Reported in Greater than or Equal to 10% of Patients with Indolent NHL Treated with Zydelig 150 mg BID
Table 7 Hematologic and Hepatic Laboratory Abnormalities in Patients with Indolent non-Hodgkin Lymphoma Treated with Zydelig 150 mg BID
Summary of Discontinued Clinical Trials in First-Line CLL and Early Line iNHL
Safety 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 6 cycles of BR with or without Zydelig 150 mg twice daily.
In Study 313-0124 (NCT01732913), 295 patients with previously treated iNHL received 8 doses of R with or without Zydelig 150 mg twice daily. Patients had a median of one prior therapy.
In Study 313-0125 (NCT01732926), 475 patients with previously treated iNHL received up to 6 cycles of BR with or without Zydelig 150 mg twice daily. Patients had a median of two prior therapies.
These three studies were terminated early due to a higher incidence of fatal and/or serious adverse reactions observed in patients treated with Zydelig in combination with R or BR. The most frequent serious adverse reactions were in the system organ classes of infections and infestations, blood and lymphatic system disorders, and gastrointestinal disorders.
7 Drug Interactions
7.1 Effects of Other Drugs on Zydelig(Additions and/or revisions are underlined)
Table 8 Drug Interactions with Zydelig that affect Idelalisib Concentrations (Table has been added; please refer to label)
(Additions and/or revisions are underlined)
The coadministration of Zydelig with a CYP3A substrate may increase the concentrations of this CYP3A substrate. Avoid coadministration of Zydelig with sensitive CYP3A substrates.
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)
Risk Summary
Based on findings in animal studies and the mechanism of action, Zydelig may cause fetal harm when administered to a 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 dose of 150 mg twice daily.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies in the U.S. general population.
Data
Animal Data
In 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…
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)
Risk Summary
No data are available regarding 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 from Zydelig in a breastfed child, advise lactating women not to breastfeed while taking Zydelig and for at least 1 month after the last dose.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)
Pregnancy
Based on animal studies, Zydelig may cause fetal harm when administered to a pregnant woman. Females of reproductive potential should have a pregnancy test prior to starting treatment with Zydelig.
Contraception
Females
Based on animal studies, Zydelig can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Zydelig and for at least 1 month after the last dose.
Males
Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of Zydelig.
(Additions and/or revisions are underlined)
In clinical trials of Zydelig in 615 patients with FL, SLL, and CLL, 327 (53%) patients were age 65 and older. No major differences in effectiveness were observed. When comparing patients 65 years of age or older to younger patients with indolent non- Hodgkin lymphoma, 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%). When comparing patients 65 years of age or older to younger patients with CLL, older patients had a 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%).
(Additions and/or revisions are underlined)
Dose adjustment is not recommended for patients with ALT or AST or bilirubin greater than or equal to upper limit of normal (ULN); however, limited safety and efficacy data are available for patients with baseline AST or ALT greater than or equal to 2.5 x ULN or bilirubin greater than or equal to 1.5 x ULN…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Embryo-Fetal Toxicity - Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 1 month after receiving the last dose of Zydelig. Advise lactating women not to breastfeed during treatment with Zydelig and for at least 1 month after the last dose.
(Additions and/or revisions are underlined)
What is the most important information I should know about Zydelig?
Zydelig can cause serious side effects that can lead to death, including:
Lung problems (pneumonitis)… Your doctor may treat you with a corticosteroid medicine if you develop lung problems.
What is Zydelig?
…
Zydelig should not be used in combination with bendamustine and/or rituximab to treat people with FL.
Before taking Zydelig, tell your doctor about all of your medical conditions, including if you:
are pregnant or plan to become pregnant. Zydelig may harm your unborn baby. Females who are able to become pregnant should have a pregnancy test before starting 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 3 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 1 month after the last dose.
What are the possible side effects of Zydelig?
…
The most common side effects of Zydelig when used in combination with rituximab or with bendamustine and rituximab include:…
What are the ingredients in Zydelig?
…
Inactive ingredients: microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate, and magnesium stearate. The tablet coating contains polyethylene glycol, talc, polyvinyl alcohol, titanium dioxide and FD&C Yellow #6 or Sunset Yellow FCF Aluminum Lake (for the 100 mg tablet) and red iron oxide (for the 150 mg tablet).
09/21/2016 (SUPPL-4)
Boxed Warning
WARNING: FATAL AND SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS, and INTESTINAL PERFORATION (additions and revisions are underlined)See full prescribing information for complete boxed warning.
Fatal and/or serious hepatotoxicity occurred in 11% to 18% of Zydelig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Zydelig.
Fatal and/or serious and severe diarrhea or colitis occurred in 14% to 19% of Zydelig-treated patients. Monitor for the development of severe diarrhea or colitis. Interrupt and then reduce or discontinue Zydelig.
Fatal and/or serious pneumonitis occurred in 4% Zydelig-treated patients. Monitor for pulmonary symptoms and bilateral interstitial infiltrates. Interrupt or discontinue Zydelig.
Fatal and/or serious infections occurred in 21% to 36% of Zydelig-treated patients. Monitor for signs and symptoms of infection. Interrupt Zydelig if infection is suspected.
5 Warnings and Precautions
5.1 HepatotoxicityFatal and/or serious hepatotoxicity occurred in 18% of patients treated with Zydelig monotherapy and 11% of patients treated with Zydelig in combination trials.
Severe diarrhea or colitis (Grade 3 or higher) occurred in 14% of patients treated with Zydelig monotherapy and 19% of patients treated with Zydelig in combination trials… Zydelig and other drugs that cause diarrhea…Diarrhea due to Zydelig responds poorly to antimotility agents…
Fatal and serious pneumonitis occurred in patients treated with Zydelig... 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.
Fatal and/or serious infections occurred in 21% of patients treated with Zydelig monotherapy and 36% of patients treated with Zydelig in combination trials. The most common infections were pneumonia, sepsis, and febrile neutropenia. Monitor patients for signs and symptoms of infection and interrupt Zydelig for Grade 3 or higher infection.
Serious or fatal Pneumocystis jirovecii pneumonia (PJP) or cytomegalovirus (CMV) occurred in less than1% of patients treated with Zydelig. Consider prophylaxis for PJP. Interrupt Zydelig in patients with suspected PJP infection of any grade, and permanently discontinue Zydelig if PJP infection of any grade is confirmed. Interrupt Zydelig in the setting of positive CMV PCR or antigen test until the infection has resolved. If Zydelig is subsequently resumed, patients should be monitored (by PCR or antigen test) for CMV reactivation at least monthly.
Fatal cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have occurred in patients treated with Zydelig. If SJS or TEN is suspected, interrupt Zydelig until the etiology of the reaction has been determined. If SJS or TEN is confirmed, permanently discontinue Zydelig.
Other severe or life-threatening (Grade greater than or equal to 3) cutaneous reactions…
Treatment-emergent Grade 3 or 4 neutropenia occurred in 25% of patients treated with Zydelig monotherapy and 46% of patients treated with Zydelig in combination trials. Monitor blood counts at least every 2 weeks for the first 6 months of therapy, and at least weekly in patients while neutrophil counts are less than 1.0 Gi/L.
6 Adverse Reactions
The following serious adverse reactions have been associated with Zydelig in clinical trials and are discussed in greater detail in other sections of the prescribing information.
Addition of:
Infections
Summary of Clinical Trials in Chronic Lymphocytic Leukemia
… 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…
Forty-two subjects (38%) had dose interruptions… reasons for dose interruptions or reductions were pneumonia, diarrhea or colitis, rash, and elevated transamines.
Table 2: Adverse Reactions Reported in greater than or equal to 5% of Patients with CLL and which Occurred at greater than or equal to 2% Higher Incidence in Subjects Receiving Zydelig
Data in table has extensively changed; please refer to label.
Table 3: Treatment-emergent Laboratory Abnormalities Reported in greater than or equal to 10% of CLL Patients Occurring at a greater than or equal to 5% Higher Incidence in Subjects Receiving Zydelig
Data in table has extensively changed; please refer to label.
The following has been added following Table 3:
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%).
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)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication GuideWhat is the most important information I should know about Zydelig?
Zydelig 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 …
Infections. Zydelig can cause serious infections that may lead to death. Tell your doctor right away if you have a fever or any signs of an infection while taking Zydelig.
Severe diarrhea. Diarrhea is common during treatment with Zydelig …
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 mouth
severe rash with blisters or peeling skin
rash with itching
What is Zydelig? (additions)
Chronic Lymphocytic Leukemia (CLL) in combination with rituximab when CLL comes back after prior cancer treatment and when rituximab treatment …
Zydelig should not be used as the first medicine to treat people who have been diagnosed with CLL, FL, or SLL.
Do not take Zydelig if you have a history of serious allergic reactions including a severe skin reaction called toxic epidermal necrolysis (TEN).
What should I tell my doctor before taking Zydelig?
Before taking Zydelig, tell your doctor about all of your medical conditions, including if you:
have an infection (addition)
are pregnant or plan to become pregnant. Zydelig may harm your unborn baby. Females who are able to become pregnant should use effective birth control (contraception) during treatment with Zydelig and for at least 1 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.
What are the possible side effects of Zydelig:
Low white blood cell count (neutropenia). Neutropenia is common during treatment with Zydelig and can sometimes be severe.
The most common side effects of Zydelig when used alone include:
tiredness
nausea
cough
fever
stomach area (abdomen) pain
pneumonia
rash
The most common side effects of Zydelig when used in combination with rituximab include:
pneumonia
fever
tiredness
rash
cough
nausea
Physicians and health care professionals are advised to discuss the following with patients prior to treatment with Zydelig:
Infections. Advise patients that Zydelig can cause serious infections that may be fatal. Advise patients to immediately report symptoms of infection (e.g. pyrexia).