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
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
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
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)
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.
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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.