What is Zydelig, and how does it work?

Relapsed Chronic Lymphocytic Leukemia

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

Limitation Of Use

Zydelig is not indicated and is not recommended for first line treatment of patients with CLL.

Relapsed Follicular B-cell Non-Hodgkin Lymphoma

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

Accelerated approval was granted for this indication based on Overall Response Rate. 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.

Limitation Of Use

Zydelig 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.

Relapsed Small Lymphocytic Lymphoma

Zydelig is indicated for the treatment of patients with relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies.

Accelerated approval was granted for this indication based on Overall Response Rate. 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.

Limitation Of Use

Zydelig is not indicated and is not recommended for first line treatment of patients with SLL.

What are the side effects of Zydelig?

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.

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.

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.

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.

Fatal and serious intestinal perforation can occur in Zydelig-treated patients across clinical trials. Discontinue Zydelig for intestinal perforation.

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
  • Severe Diarrhea or Colitis
  • Pneumonitis
  • Infections
  • Intestinal Perforation
  • Severe Cutaneous Reactions
  • Anaphylaxis
  • Neutropenia

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 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. 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 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 ≥5% of Patients with CLL and Occurred at ≥2% Higher Incidence in Patients Receiving Zydelig in Study 312-0116

Adverse Reaction Zydelig + R
N=110 (%)
Placebo + R
N=108(%)
Any Grade Grade ≥3 Any Grade Grade ≥3
General disorders and administration site conditions
pyrexia 44 (40) 3 (3) 20 (19) 1 (1)
chills 27 (25) 2 (2) 17 (16) 0
pain 8 (7) 0 1 (1) 0
Gastrointestinal disorders
diarrhea (a) 35 (32) 12 (11) 20 (19) 0
nausea 30 (27) 1 (1) 25 (23) 0
abdominal pain (b) 20 (18) 1 (1) 17 (16) 2 (2)
vomiting 17 (15) 0 9 (8) 0
gastroesophageal reflux disease 11 (10) 1 (1) 0 0
stomatitis 7 (6) 2 (2) 1 (1) 0
Respiratory, thoracic, and mediastinal disorders
pneumonia (c) 33 (30) 23 (21) 20 (19) 14 (13)
Skin and subcutaneous tissue disorders
rash (d) 27 (25) 4 (4) 7 (6) 1 (1)
Metabolism and Nutrition Disorders
decreased appetite 18 (16) 2 (2) 12 (11) 2 (2)
dehydration 7 (6) 3 (3) 0 0
Infections and infestations
sepsis (e) 10 (9) 10 (9) 4 (4) 4 (4)
sinusitis 9 (8) 0 6 (6) 0
urinary tract infection 9 (8) 1 (1) 4 (4) 2 (2)
bronchitis 8 (7) 1 (1) 5 (5) 1 (1)
oral herpes 6 (5) 1 (1) 3 (3) 0
Psychiatric disorders
insomnia 10 (9) 0 7 (6) 0
Musculoskeletal and connective tissue disorders
arthralgia 9 (8) 1 (1) 4 (4) 0
Nervous system disorders
lethargy 6 (5) 0 2 (2) 0
(a) Diarrhea includes the following preferred terms: diarrhea, colitis.
(b) Abdominal pain includes the following preferred terms: abdominal pain, abdominal pain upper, abdominal pain lower.
(c) Pneumonia includes the terms: pneumonia, pneumonitis, lung infection, lung infiltration, pneumocystis jiroveci pneumonia, pneumonia legionella, lung infection pseudomonal, pneumonia fungal, respiratory tract infection, lower respiratory tract infection, and lower respiratory tract infection bacterial.
(d) 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.
(e) Sepsis includes the terms: sepsis, septic shock, neutropenic sepsis, and sepsis syndrome

Table 3 : Hematologic and Hepatic Laboratory Abnormalities Reported in ≥10% of Patients with CLL and Occurred at ≥5% Higher Incidence in Patients Receiving Zydelig in Study 312-0116

Laboratory Parameter Zydelig + R
N=110(%)
Placebo + R
N=108 (%)
Any Grade Grade 3-4 Any Grade Grade 3-4
Hematology abnormalities
neutropenia 71 (65) 46 (42) 61 (56) 33 (31)
leukopenia 34 (31) 9 (8) 25 (23) 9 (8)
lymphocytopenia 23 (21) 11 (10) 13 (12) 4 (4)
Serum chemistry abnormalities
ALT increased 43 (39) 10 (9) 13 (12) 1 (1)
AST increased 31 (28) 6 (5) 16 (15) 0

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. 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%).
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 146 patients 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. 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 4 provides the adverse reactions occurring in at least 10% of patients receiving Zydelig monotherapy, and Table 5 provides the hematologic and hepatic laboratory abnormalities.

Table 4 : Adverse Reactions Reported in ≥ 10% of Patients with Indolent NHL Treated with Zydelig 150 mg BID

Adverse Reaction Zydelig Monotherapy
N=146(%)
Any Grade Grade ≥3
Gastrointestinal disorders
diarrhea (a) 68 (47) 20 (14)
nausea 42 (29) 2 (1)
abdominal pain (b) 38 (26) 3 (2)
vomiting 22 (15) 2 (1)
General disorders and administration site conditions
fatigue 44 (30) 2 (1)
pyrexia 41 (28) 3 (2)
asthenia 17 (12) 3 (2)
peripheral edema 15 (10) 3 (2)
Respiratory, thoracic, and mediastinal disorders
cough 42 (29) 1 (1)
pneumonia (c) 37 (25) 23 (16)
dyspnea 25 (17) 6 (4)
Skin and subcutaneous disorders
rash (d) 31 (21) 4 (3)
night sweats 18 (12) 0
Metabolism and nutrition disorders
decreased appetite 24 (16) 1 (1)
Infections and infestations
upper respiratory tract infection 18 (12) 0
Psychiatric disorders
insomnia 17 (12) 0
Nervous system disorders
headache 16 (11) 1 (1)
(a) Diarrhea includes the following preferred terms: diarrhea, colitis, enterocolitis, and gastrointestinal inflammation.
(b) Abdominal pain includes the following preferred terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort.
(c) Pneumonia includes the terms: pneumonia, pneumonitis, interstitial lung disease, lung infiltration, pneumonia aspiration, respiratory tract infection, atypical pneumonia, lung infection, pneumocystis jiroveci pneumonia, bronchopneumonia, pneumonia necrotizing, lower respiratory tract infection, pneumonia pneumococcal, pneumonia staphylococcal, pneumonia streptococcal, pneumonia cytomegaloviral, and respiratory syncytial virus infection.
(d) Rash includes the following preferred terms: dermatitis exfoliative, rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, and exfoliative rash.

Table 5 : Hematologic and Hepatic Laboratory Abnormalities in Patients with Indolent non-Hodgkin Lymphoma Treated with Zydelig 150 mg BID

Laboratory Abnormality Zydelig Monotherapy
N=146(%)
Any Grade Grade 3 Grade 4
Serum chemistry abnormalities
ALT increased 73 (50) 20 (14) 7 (5)
AST increased 60 (41) 12 (8) 6 (4)
Hematology abnormalities
neutrophils decreased 78 (53) 20 (14) 16 (11)
hemoglobin decreased 41 (28) 3 (2) 0
platelets decreased 38 (26) 4 (3) 5 (3)
Grades were obtained per CTCAE version 4.03.

Summary Of Discontinued Clinical Trials In First-Line CLL and Early Line iNHL
  • Safety data described below reflect exposure to Zydelig in three randomized, doubleblind 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.

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)

QUESTION

What is leukemia? See Answer

What is the dosage for Zydelig?

Recommended Dosage

  • The recommended maximum starting dose of Zydelig is 150 mg administered orally twice daily.
  • Zydelig can be taken with or without food. Tablets should be swallowed whole.
  • Continue treatment until disease progression or unacceptable toxicity. The optimal and safe dosing regimen for patients who receive treatment longer than several months is unknown.

Dose Modification

See Table 1 for dose modification instructions for specific toxicities related to Zydelig. For other severe or life-threatening toxicities related to Zydelig, withhold drug until toxicity is resolved. If resuming Zydelig after interruption for other severe or lifethreatening toxicities, reduce the dose to 100 mg twice daily. Discontinue Zydelig permanently for recurrence of other severe or life-threatening Zydelig-related toxicity upon rechallenge.

Table 1 : Dose Modifications for Toxicities Due to Zydelig

Pneumonitis Any symptomatic pneumonitis
Discontinue Zydelig in patients with any severity of symptomatic pneumonitis
ALT/AST >3-5 x ULN >5-20 x ULN >20 x ULN
  Maintain Zydelig dose. Monitor at least weekly until ≤1 x ULN. Withhold Zydelig. Monitor at least weekly until ALT/AST are ≤1 x ULN, then may resume Zydelig at 100 mg BID. Discontinue Zydelig permanently.
Bilirubin >1.5-3 x ULN >3-10 x ULN >10 x ULN
  Maintain Zydelig dose. Monitor at least weekly until ≤1 x ULN. Withhold Zydelig. Monitor at least weekly until bilirubin is ≤1 x ULN, then may resume Zydelig at 100 mg BID. Discontinue Zydelig permanently.
Diarrhea* Moderate diarrhea Severe diarrhea or hospitalization Life-threatening diarrhea
  Maintain Zydelig dose. Monitor at least weekly until resolved. Withhold Zydelig. Monitor at least weekly until resolved, then may resume Zydelig at 100 mg BID. Discontinue Zydelig permanently.
Neutropenia ANC 1.0 to <1.5 Gi/L ANC 0.5 to <1.0 Gi/L ANC <0.5 Gi/L
  Maintain Zydelig dose. Maintain Zydelig dose. Monitor ANC at least weekly. Interrupt Zydelig. Monitor ANC at least weekly until ANC ≥0.5 Gi/L, then may resume Zydelig at 100 mg BID.
Thrombocytopenia Platelets 50 to <75 Gi/L Platelets 25 to <50 Gi/L Platelets <25 Gi/L
  Maintain Zydelig dose. Maintain Zydelig dose. Monitor platelet counts at least weekly. Interrupt Zydelig. Monitor platelet count at least weekly. May resume Zydelig at 100 mg BID when platelets ≥25 Gi/L.
Infections Grade 3 or higher sepsis or pneumonia
  Interrupt Zydelig until infection has resolved.
Evidence of CMV infection or viremia
Interrupt 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 infection
  Interrupt Zydelig in patients with suspected PJP infection of any grade. Permanently discontinue Zydelig if PJP infection is confirmed.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; ULN, upper limit of normal; CMV, cytomegalovirus; PCR: polymerase chain reaction; PJP: Pneumocystis jirovecii pneumonia
*Moderate diarrhea: increase of 4–6 stools per day over baseline; severe diarrhea: increase of ≥7 stools per day over baseline.

No dose modification is required for lymphocytosis, which has been observed in some patients taking Zydelig. This observed lymphocytosis is a pharmacodynamic effect and should not be considered progressive disease in the absence of other clinical findings.

What drugs interact with Zydelig?

Effects Of Other Drugs On Zydelig

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

Strong CYP3A Inhibitors
Clinical Impact
  • Coadministration with strong CYP3A inhibitors may increase idelalisib concentrations.
  • Increased idelalisib concentrations may increase the risk of exposure related adverse reactions.
Prevention or Management
  • Use other drugs that are not strong CYP3A inhibitors.
  • If unable to use alternative drugs, monitor patients more frequently for Zydelig adverse reactions.
Strong CYP3A Inducers
Clinical Impact
  • Coadministration with strong CYP3A inducers may decrease idelalisib concentrations.
  • Decreased idelalisib concentrations may reduce efficacy.
Prevention or Management
  • Avoid coadministration of Zydelig with strong CYP3A4 inducers.

Effects Of Zydelig On Other Drugs

The coadministration of Zydelig with a CYP3A substrate may increase the concentrations of this CYP3A substrate. Avoid coadministration of Zydelig with sensitive CYP3A substrates.

Is Zydelig safe to use while pregnant or breastfeeding?

  • Based on findings in animal studies (see Data) 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.
  • 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.

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Summary

Zydelig is a prescription medication used to treat relapsed forms of chronic lymphocytic leukemia (CLL), follicular B-cell non- Hodgkin lymphoma (FL), and small lymphocytic lymphoma (SLL). Zydelig is not indicated and is not recommended as a first-line treatment. Serious side effects of Zydelig include fatal and/or serious hepatotoxicity, severe diarrhea, pneumonitis, infections, and intestinal perforation.

Treatment & Diagnosis

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Medically Reviewed on 11/2/2020
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All sections courtesy of the U.S. Food and Drug Administration