WARNING: FATAL AND
SERIOUS TOXICITIES: HEPATIC, SEVERE DIARRHEA, COLITIS, PNEUMONITIS, INFECTIONS,
and INTESTINAL PERFORATION
· 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 as recommended [see Dosage and
Administration (2.2), Warnings and
Precautions (5.1)].
· Fatal and/or serious
and severe diarrhea or colitis occurred in 14% to 19% of Zydelig-treated
patients. Monitor for the development of severe diarrhea or colitis. Interrupt
and then reduce or discontinue Zydelig as recommended [see Dosage and Administration (2.2), Warnings and Precautions (5.2)].
· Fatal and/or serious
pneumonitis occurred in 4% of Zydelig-treated patients. Monitor for pulmonary
symptoms and bilateral interstitial infiltrates. Interrupt or discontinue
Zydelig as recommended [see Dosage and
Administration (2.2), Warnings and
Precautions (5.3)].
· Fatal and/or serious
infections occurred in 21% to 36% 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)].
Indications and Usage for ZydeligRelapsed 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 [see Clinical Studies (14.2)]. An improvement in
patient survival or disease related symptoms has not been established.
Continued approval for this indication may be contingent upon verification of
clinical benefit in confirmatory trials.
Limitation of Use
Zydelig is not indicated and
is not recommended for first line treatment of patients with 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 [see Clinical Studies (14.3)]. An improvement in
patient survival or disease related symptoms has not been established.
Continued approval for this indication may be contingent upon verification of
clinical benefit in confirmatory trials.
Limitation of Use
Zydelig is not indicated and
is not recommended for first line treatment of patients with SLL.
Zydelig Dosage and AdministrationRecommended 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 the table below 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 life-threatening toxicities, reduce the dose to 100 mg twice daily.
Recurrence of other severe or life-threatening Zydelig-related toxicity upon
rechallenge should result in permanent discontinuation of Zydelig.
Table 1 Dose Modifications for Toxicities
Due to Zydelig
|
|
*
Moderate diarrhea: increase of 4–6 stools per day
over baseline; severe diarrhea: increase of ≥7 stools per day over baseline.
|
|
Pneumonitis
|
Any symptomatic pneumonitis
|
|
|
Discontinue Zydelig in patients with any severity of
symptomatic pneumonitis
|
|
ALT/AST
|
>3–5 × ULN
|
>5–20 × ULN
|
>20 × ULN
|
|
|
Maintain Zydelig dose. Monitor at least weekly until
≤1 × ULN.
|
Withhold Zydelig.
Monitor at least weekly until ALT/AST are ≤1 × ULN, then may resume Zydelig
at 100 mg BID.
|
Discontinue Zydelig permanently.
|
|
Bilirubin
|
>1.5–3 × ULN
|
>3–10 × ULN
|
>10 × ULN
|
|
|
Maintain Zydelig dose. Monitor at least weekly until
≤1 × ULN.
|
Withhold Zydelig. Monitor at least weekly until
bilirubin is ≤1 × ULN, then may resume Zydelig at 100 mg BID.
|
Discontinue Zydelig permanently.
|
|
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 CMV
infection of any grade or viremia (positive PCR or antigen test) until the
infection 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
|
Dosage Forms and Strengths
150 mg tablets: pink,
oval-shaped, film-coated tablet debossed with "GSI" on one side and
"150" on the other side.
100 mg tablets: orange,
oval-shaped, film-coated tablet debossed with "GSI" on one side and
"100" on the other side.
Contraindications
History of serious allergic
reactions including anaphylaxis and toxic epidermal necrolysis.
Warnings and PrecautionsHepatotoxicity
Fatal and/or serious
hepatotoxicity occurred in 18% of patients treated with Zydelig monotherapy and
11% of patients treated with Zydelig in combination trials. Elevations in ALT
or AST greater than 5 times the upper limit of normal have occurred [see Adverse Reactions (6.1)]. These findings were
generally observed within the first 12 weeks of treatment and were reversible
with dose interruption. After resumption of treatment at a lower dose, 26% of
patients had recurrence of ALT and AST elevations. Discontinue Zydelig for
recurrent hepatotoxicity.
Avoid concurrent use of
Zydelig with other drugs that may cause liver toxicity.
Monitor ALT and AST in all
patients every 2 weeks for the first 3 months of treatment, every 4 weeks for
the next 3 months, then every 1 to 3 months thereafter. Monitor weekly for
liver toxicity if the ALT or AST rises above 3 times the upper limit of normal
until resolved. Withhold Zydelig if the ALT or AST is greater than 5 times the
upper limit of normal, and continue to monitor AST, ALT and total bilirubin
weekly until the abnormality is resolved [see Dosage
and Administration (2.2)].
Severe Diarrhea or Colitis
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 [see Adverse
Reactions (6.1)]. Diarrhea can occur at any time. Avoid concurrent use of
Zydelig and other drugs that cause diarrhea. Diarrhea due to Zydelig responds
poorly to antimotility agents. Median time to resolution ranged between 1 week
and 1 month across trials, following interruption of Zydelig therapy and in
some instances, use of corticosteroids [see Dosage
and Administration (2.2)].
Pneumonitis
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. 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 should be
evaluated for pneumonitis. If pneumonitis is suspected, interrupt Zydelig until
the etiology of the pulmonary symptoms has been determined. Patients with
pneumonitis thought to be caused by Zydelig have been treated with
discontinuation of Zydelig and administration of corticosteroids.
Infections
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 [see Dosage
and Administration (2.2)].
Serious or fatal Pneumocystis jirovecii pneumonia (PJP) or
cytomegalovirus (CMV) occurred in <1% 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 [see Dosage
and Administration (2.2)].
Intestinal Perforation
Fatal and serious intestinal
perforation occurred in Zydelig-treated patients. At the time of perforation,
some patients had moderate to severe diarrhea. Advise patients to promptly
report any new or worsening abdominal pain, chills, fever, nausea, or vomiting.
Discontinue Zydelig permanently in patients who experience intestinal
perforation.
Severe Cutaneous Reactions
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 ≥3) cutaneous reactions, including dermatitis
exfoliative, rash, rash erythematous, rash generalized, rash macular, rash
maculo-papular, rash papular, rash pruritic, exfoliative rash, and skin disorder,
have been reported in Zydelig-treated patients. Monitor patients for the
development of severe cutaneous reactions and discontinue Zydelig.
Anaphylaxis
Serious allergic reactions,
including anaphylaxis, have been reported in patients on Zydelig. In patients
who develop serious allergic reactions, discontinue Zydelig permanently and
institute appropriate supportive measures.
Neutropenia
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 [see Dosage and
Administration (2.2)].
Embryo-fetal Toxicity
Based on findings in animals,
Zydelig may cause fetal harm when administered to a pregnant woman. Idelalisib
is teratogenic in rats, at systemic exposures 12 times those reported in
patients at the recommended dose of 150 mg twice daily. 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 [see Use in Specific
Populations (8.1)].
Advise females of reproductive
potential to avoid becoming pregnant while taking Zydelig. If contraceptive
methods are being considered, use effective contraception during treatment, and
for at least 1 month after the last dose of Zydelig [see Use in
Specific Populations (8.6)].
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.
·
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.
Table 2 Adverse Reactions Reported in ≥5% of Patients with CLL and
which Occurred at ≥2% Higher Incidence in Subjects Receiving Zydelig
|
|
|
Zydelig + Rituximab
N=110 (%)
|
Placebo + Rituximab
N=108 (%)
|
|
Adverse
Reaction
|
Any Grade
|
Grade ≥3
|
Any Grade
|
Grade ≥3
|
|
*
Diarrhea
includes the following preferred terms: diarrhea, colitis.
†
Abdominal pain
includes the following preferred terms: abdominal pain, abdominal pain upper,
abdominal pain lower.
‡
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 morbiliform, and exfoliative rash.
§
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.
¶
Sepsis includes the terms: sepsis, septic shock,
neutropenic sepsis, and sepsis syndrome.
|
|
Gastrointestinal
disorders
|
|
diarrhea *
|
35 (32)
|
12 (11)
|
20 (19)
|
0
|
|
nausea
|
30 (27)
|
1 (1)
|
25 (23)
|
0
|
|
abdominal
pain †
|
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
|
|
Nervous system
disorders
|
|
lethargy
|
6 (5)
|
0
|
2 (2)
|
0
|
|
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
|
|
Skin and
subcutaneous tissue disorders
|
|
rash ‡
|
27 (25)
|
4 (4)
|
7 (6)
|
1 (1)
|
|
Respiratory,
thoracic, and mediastinal disorders
|
|
pneumonia §
|
33 (30)
|
23 (21)
|
20 (19)
|
14 (13)
|
|
Infections and
infestations
|
|
sepsis ¶
|
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
|
|
Musculoskeletal
and connective tissue disorders
|
|
arthralgia
|
9 (8)
|
1 (1)
|
4 (4)
|
0
|
|
Metabolism and
Nutrition Disorders
|
|
decreased
appetite
|
18 (16)
|
2 (2)
|
12 (11)
|
2 (2)
|
|
dehydration
|
7 (6)
|
3 (3)
|
0
|
0
|
|
Psychiatric
disorders
|
|
insomnia
|
10 (9)
|
0
|
7 (6)
|
0
|
Table 3 Treatment-emergent Laboratory Abnormalities Reported in ≥10%
of CLL Patients Occurring at a ≥5% Higher Incidence in Subjects Receiving
Zydelig
|
|
|
Zydelig + Rituximab
N=110 (%)
|
Placebo + Rituximab
N=108 (%)
|
|
Laboratory
Parameter
|
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 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.
Table 4 Adverse Reactions (≥ 10% of Subjects) in Patients with
Indolent non-Hodgkin Lymphoma Treated with Zydelig 150 mg BID
|
|
|
Zydelig Monotherapy
N=146 (%)
|
|
Adverse
Reaction
|
Any Grade
|
Grade ≥3
|
|
*
Diarrhea
includes the following preferred terms: diarrhea, colitis, enterocolitis, and
gastrointestinal inflammation.
†
Abdominal pain
includes the following preferred terms: abdominal pain, abdominal pain upper,
abdominal pain lower, and abdominal discomfort.
‡
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.
§
Rash includes the following preferred terms:
dermatitis exfoliative, rash, rash erythematous, rash macular, rash
maculo-papular, rash pruritic, and exfoliative rash.
|
|
Gastrointestinal
disorders
|
|
diarrhea *
|
68 (47)
|
20 (14)
|
|
nausea
|
42 (29)
|
2 (1)
|
|
abdominal
pain †
|
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)
|
|
Infections and
infestations
|
|
upper
respiratory tract infection
|
18 (12)
|
0
|
|
Respiratory,
thoracic, and mediastinal disorders
|
|
pneumonia ‡
|
37 (25)
|
23 (16)
|
|
cough
|
42 (29)
|
1 (1)
|
|
dyspnea
|
25 (17)
|
6 (4)
|
|
Skin and
subcutaneous disorders
|
|
rash §
|
31 (21)
|
4 (3)
|
|
night
sweats
|
18 (12)
|
0
|
|
Nervous system
disorders
|
|
|
|
headache
|
16 (11)
|
1 (1)
|
|
Metabolism and
nutrition disorders
|
|
decreased
appetite
|
24 (16)
|
1 (1)
|
|
Psychiatric disorders
|
|
|
|
insomnia
|
17 (12)
|
0
|
Table 5 Treatment-emergent Laboratory Abnormalities in Patients with
Indolent non-Hodgkin Lymphoma Treated with Zydelig 150 mg BID
|
|
|
Zydelig Monotherapy
N=146 (%)
|
|
Laboratory
Abnormality
|
Any Grade
|
Grade 3
|
Grade 4
|
|
Grades were
obtained per CTCAE version 4.03.
|
|
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)
|
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)
Drug InteractionsEffects 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)].
USE IN SPECIFIC POPULATIONSPregnancy
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)].
Zydelig Description
Idelalisib is an inhibitor of
phosphatidylinositol 3-kinase, PI3Kδ.
The chemical name for
idelalisib is 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one. It has a molecular formula of C22H18FN7O and a molecular weight of
415.42 g/mol. Idelalisib has the following structural formula:
Idelalisib is a white to
off-white solid with a pH-dependent aqueous solubility ranging from <0.1
mg/mL at pH 5–7 to over 1 mg/mL at pH 2 under ambient conditions.
Zydelig (idelalisib) tablets
are for oral administration. Each tablet contains either 100 mg or 150 mg of
idelalisib with the following inactive ingredients: microcrystalline cellulose,
hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate,
magnesium stearate and a tablet coating. The tablet coating consists of
polyethylene glycol, talc, polyvinyl alcohol, and titanium dioxide and of
FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake (for the 100 mg tablet) and
red iron oxide (for the 150 mg tablet).
Zydelig - Clinical PharmacologyMechanism of Action
Idelalisib is an inhibitor of
PI3Kδ kinase, which is expressed in normal and malignant B-cells. Idelalisib
induced apoptosis and inhibited proliferation in cell lines derived from
malignant B-cells and in primary tumor cells. Idelalisib inhibits several cell
signaling pathways, including B-cell receptor (BCR) signaling and the CXCR4 and
CXCR5 signaling, which are involved in trafficking and homing of B-cells to the
lymph nodes and bone marrow. Treatment of lymphoma cells with idelalisib
resulted in inhibition of chemotaxis and adhesion, and reduced cell viability.
Pharmacodynamics
Electrocardiographic
Effects
The effect of Zydelig (150 mg
and 400 mg) on the QT/QTc interval was evaluated in a placebo- and
positive-controlled (moxifloxacin 400 mg) crossover study in 46 healthy
subjects. At a dose 2.7 times the maximum recommended dose, Zydelig did not
prolong the QT/QTc interval (i.e., not greater than or equal to 10 ms).
Pharmacokinetics
Absorption
Following oral administration
of a single dose of Zydelig in the fasted state, the median Tmax was observed at 1.5
hours.
Idelalisib exposure increased
in a less than dose-proportional manner over a dose range of 50 mg to 350 mg
twice daily in the fasted state.
Relative to fasting
conditions, the administration of a single dose of Zydelig with a high-fat meal
increased idelalisib AUC 1.4-fold. Zydelig can be administered without regard
to food.
Distribution
Idelalisib is greater than 84%
bound to human plasma proteins with no concentration dependence. The mean
blood-to-plasma ratio was 0.7. The population apparent central volume of
distribution at steady state is 23 L.
Metabolism
and Elimination
Idelalisib is metabolized to
its major metabolite GS-563117 via aldehyde oxidase and CYP3A. GS-563117 is
inactive against PI3Kδ in vitro. Idelalisib undergoes minor metabolism by
UGT1A4.
The population apparent
systemic clearance at steady-state is 14.9 L/hr. The population terminal
elimination half-life of idelalisib is 8.2 hours. Following a single dose of
150 mg of [14C] idelalisib, 78% and 14% of the radioactivity was excreted in
feces and urine, respectively. GS-563117 accounted for 49% of the radioactivity
in the urine and 44% in the feces.
Specific
Populations
Age, Gender, Race, and Weight
Population pharmacokinetic
analyses indicated that age, gender, race, and weight had no effect on
idelalisib exposure.
Pediatric Patients
The pharmacokinetics of
idelalisib has not been studied in pediatric patients.
Patients with Renal Impairment
A pharmacokinetic study
following a single dose of 150 mg of Zydelig was performed in healthy subjects
and subjects with severe renal impairment (CrCl 15 to 29 mL/min). Creatinine
clearance had no effect on idelalisib exposure. No dose adjustment is needed
for patients with CrCl ≥15 mL/min.
Patients with Hepatic Impairment
A pharmacokinetic study of
Zydelig was performed in healthy subjects and subjects with hepatic impairment.
The geometric mean AUC increased up to 1.7-fold in subjects with ALT or AST or
bilirubin values greater than the upper limit of normal (ULN) compared to
subjects with normal AST or ALT or bilirubin values. Limited safety and
efficacy data are available for patients with baseline AST or ALT greater than
2.5 × ULN or bilirubin 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 Boxed
Warning and Warnings
and Precautions (5.1)]. Follow dose
modifications for adverse reactions [see Dosage
and Administration (2.2)].
Drug
Interactions
In Vitro Studies
Idelalisib is a substrate for
aldehyde oxidase, CYP3A, and UGT1A4 in vitro.
Idelalisib inhibits CYP2C8,
CYP2C19, CYP3A, and UGT1A1 and GS-563117 inhibits CYP2C8, CYP2C9, CYP2C19,
CYP3A and UGT1A1 in vitro. Idelalisib and GS-563117 are not likely to inhibit
CYP1A, CYP2B6, and CYP2D6.
Idelalisib induces CYP2B6 and
CYP3A4, but does not induce CYP1A2 in vitro. GS-563117 does not induce these
enzymes.
Idelalisib and GS-563117 are
substrates of P-glycoprotein (P-gp) and BCRP in vitro. Idelalisib is not a
substrate of OATP1B1, OATP1B3, OAT1, OAT3, or OCT2. GS-563117 is not a
substrate of OATP1B1 or OATP1B3.
Idelalisib inhibits P-gp,
OATP1B1, and OATP1B3, and GS-563117 inhibits OATP1B1, OATP1B3 in vitro.
Idelalisib is not likely to inhibit BCRP, OCT2, OAT1, or OAT3, and GS-563117 is
not likely to inhibit P-gp, BCRP, OCT2, OAT1, or OAT3.
Effect of Other Drugs on Idelalisib
A single dose of 150 mg of
Zydelig was administered alone and after rifampin (a strong CYP3A and P-gp
inducer) 600 mg once daily for 8 days in healthy subjects. Rifampin decreased
the geometric mean idelalisib AUC by 75% and the geometric mean Cmax by 58%. Avoid
coadministration of Zydelig with strong CYP3A and P-gp inducers.
A single dose of 400 mg of Zydelig
was administered alone and after ketoconazole (a strong CYP3A and P-gp
inhibitor) 400 mg daily for 4 days in healthy subjects. Ketoconazole increased
the geometric mean idelalisib AUC by 1.8-fold. No changes in the geometric mean
Cmax were
observed. Patients taking concomitant CYP3A inhibitors 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)].
Effect of Idelalisib on Other Drugs
A single oral dose of
midazolam 5 mg was administered alone and after Zydelig 150 mg for 15 doses in
healthy subjects. The geometric mean midazolam Cmax increased by 2.4-fold and
the geometric mean midazolam AUC increased by 5.4-fold. Avoid coadministration
of Zydelig with CYP3A substrates, as Zydelig is a strong CYP3A inhibitor.
A single dose of 10 mg of
rosuvastatin (OATP1B1 and OATP1B3 substrate) was administered alone and after
Zydelig 150 mg for 12 doses in healthy subjects. No changes in exposure to
rosuvastatin were observed.
A single dose of 0.5 mg of
digoxin (P-gp substrate) was administered alone and after Zydelig 150 mg for 19
doses in healthy subjects. No changes in exposure to digoxin were observed.
Nonclinical ToxicologyCarcinogenesis, Mutagenesis,
Impairment of Fertility
Idelalisib was not
carcinogenic in a 26-week study in transgenic mice when administered daily by
oral gavage at doses up to 500 mg/kg/day in males and 1000 mg/kg/day in
females. Idelalisib was not carcinogenic in a 2-year study in rats when
administered daily by oral gavage at exposures 0.40/0.62-fold (male/female),
compared to the exposure in patients with hematologic malignancies administered
the recommended dose of 150 mg twice daily.
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.
Clinical StudiesRelapsed 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.
Table 6 Efficacy Results from Study 1
|
|
|
|
Zydelig + R
n=110
|
Placebo + R
n=110
|
|
R: rituximab;
PFS: progression-free survival; NR: not reached
|
|
*
The p value for PFS was based on stratified log-rank
test.
|
|
PFS
|
Median (months)
(95% CI)
|
NR (10.7, NR)
|
5.5 (3.8, 7.1)
|
|
|
Hazard ratio
(95% CI)
|
0.18 (0.10, 0.32)
|
|
|
P-value
|
< 0.0001 *
|
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.
Table 7 Overall Response Rate (ORR) and Duration of Response (DOR)
in Patients with Relapsed Follicular Lymphoma
|
|
|
N=72
|
|
CI = confidence
interval; CR = complete response; PR = partial response
|
|
*
Kaplan-Meier estimate
|
|
ORR
|
39 (54%)
|
|
95%
CI
|
(42, 66%)
|
|
CR
|
6 (8%)
|
|
PR
|
33 (46%)
|
|
Median* DOR, months (range)
|
median not
evaluable (0.0+, 14.8+)
|
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.
Table 8 Overall Response Rate (ORR) and Duration of Response (DOR)
in Patients with Relapsed Small Lymphocytic Lymphoma
|
|
|
N=26
|
|
CI = confidence
interval; CR = complete response; PR = partial response
|
|
*
Kaplan-Meier estimate
|
|
ORR
|
15 (58%)
|
|
95%
CI
|
(37, 77%)
|
|
CR
|
0
|
|
PR
|
15 (58%)
|
|
Median* DOR, months (range)
|
11.9 (0.0+,
14.7+)
|
The median time to response
was 1.9 months (range 1.6–8.3).
How Supplied/Storage and Handling
Zydelig tablets supplied as
follows:
|
Tablet
Strength
|
Package
Configuration
|
NDC No.
|
Description
of Tablet; Debossed on Tablet
|
|
150 mg
|
High density
polyethylene (HDPE) bottle with a polyester fiber coil, capped with a
child-resistant closure. Each bottle contains 60 film-coated tablets.
|
61958-1702-1
|
Oval shaped;
pink; "150" on one side and "GSI" on the other side
|
|
100 mg
|
61958-1701-1
|
Oval-shaped;
orange; "100" on one side and "GSI" on the other side
|
Store between 20–30 °C (68–86
°F) with excursions permitted 15–30 °C (59–86 °F).
·
Dispense only in original
container.
·
Do not use if seal over bottle
opening is broken or missing.
Patient Counseling Information
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.
©2017 Gilead Sciences, Inc.
All rights reserved.
205858-GS-002-PI
|
MEDICATION GUIDE
Zydelig® (zye-DEL-ig)
(idelalisib)
tablets
|
|
This Medication
Guide has been approved by the U.S. Food and Drug Administration.
|
Revised: 09 2016
|
|
What 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 before and during your treatment with Zydelig to
check for liver problems. Tell your doctor right away if you get any of the
following symptoms of liver problems:
o yellowing
of your skin or the white part of your eyes (jaundice)
o dark
or brown (tea colored) urine
o pain
in the upper right side of your stomach area (abdomen)
o bleeding
or bruising more easily than normal
· Severe diarrhea. Diarrhea is common during treatment with
Zydelig and can sometimes be severe. Tell your doctor right away if the
number of bowel movements you have in a day increases by six or more. Ask
your doctor about medicines you can take to treat your diarrhea.
· Lung or breathing problems. Your doctor may do tests to check
your lungs if you have breathing problems during treatment with Zydelig. Tell
your doctor right away if you get new or worsening cough, shortness of
breath, difficulty breathing, or wheezing.
· 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.
· Tear in intestinal wall (perforation). Tell your doctor or get medical
help right away if you get new or worsening stomach area (abdomen) pain,
chills, fever, nausea, or vomiting.
· Severe skin reactions. Tell your doctor right away if you
get any of the following symptoms during treatment with Zydelig:
o painful
sores or ulcers on your skin, lips, or in your mouth
o severe
rash with blisters or peeling skin
o rash
with itching
If you have any
of the above serious side effects during treatment with Zydelig, your doctor
may completely stop your treatment, stop your treatment for a period of time,
or change your dose of Zydelig.
See "What are the possible side effects of
Zydelig?" for more information about side effects.
|
|
What is Zydelig?
Zydelig is a prescription medicine used to treat people with:
· Chronic Lymphocytic Leukemia (CLL) in combination with rituximab when
CLL comes back after prior cancer treatment and when rituximab treatment
alone may be used due to other health problems.
· Follicular B-cell non-Hodgkin Lymphoma (FL) when the disease has come back
after treatment with at least two prior medicines.
· Small Lymphocytic Lymphoma (SLL) when the disease comes back after
treatment with at least two prior medicines.
Zydelig should
not be used as the first medicine to treat people who have been diagnosed
with CLL, FL, or SLL. It is not known if Zydelig is safe and effective in
children less than 18 years of age.
|
|
Do not take Zydelig if you have 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
liver problems
· have
lung or breathing problems
· have
an infection
· are
pregnant or plan to become pregnant. Zydelig may harm your unborn baby.
Females who are able to become pregnant should 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.
· are
breastfeeding or plan to breastfeed. It is not known if Zydelig passes into
your breast milk. You and your doctor should decide if you will take Zydelig
or breastfeed. You should not do both.
Tell your doctor about all the medicines you take, including prescription and
over-the-counter medicines, vitamins, and herbal supplements. Zydelig and
certain other medicines may affect each other.
Know the medicines you take. Keep a list of your medicines and show it to
your doctor and pharmacist when you get a new medicine.
|
|
How should I take Zydelig?
· Take
Zydelig exactly as your doctor tells you to take it.
· Your
doctor may change your dose of Zydelig or tell you to stop taking Zydelig. Do
not change your dose or stop taking Zydelig without first talking to your
doctor.
· Take
Zydelig 2 times a day.
· You
may take Zydelig with or without food.
· Take
Zydelig tablets whole.
· Do
not miss a dose of Zydelig. If you miss a dose of Zydelig by less than 6
hours, take the missed dose right away. Then take your next dose as usual. If
you miss a dose of Zydelig by more than 6 hours, wait and take the next dose
of Zydelig at your usual time.
|
|
What are the possible side effects of Zydelig?
Zydelig can cause serious side effects, including:
· See "What is the most important information
I should know about Zydelig?"
· Anaphylaxis. Tell your doctor or get medical help right
away if you have a serious allergic reaction while taking Zydelig.
· Low white blood cell count (neutropenia). Neutropenia is common during
treatment with Zydelig and can sometimes be severe. Your doctor will check
your blood counts regularly during treatment with Zydelig. Tell your doctor
right away if you have a fever or any signs of an infection while taking
Zydelig.
|
|
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
|
|
Tell your doctor
if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Zydelig. Call your doctor for
medical advice about side effects. You may report side effects to FDA at
1-800-FDA-1088.
|
|
How should I store Zydelig?
· Store
Zydelig between 68°F to 86°F (20°C to 30°C).
· Keep
Zydelig in its original container.
· Do
not use Zydelig if the seal over the bottle opening is broken or missing.
Keep Zydelig and all medicines out of reach of children.
|
|
General information about Zydelig
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use Zydelig for a condition for which it was not
prescribed. Do not give Zydelig to other people, even if they have the same
symptoms you have. It may harm them. You can ask your doctor or pharmacist
for information about Zydelig that is written for health professionals.
|
|
What are the ingredients in Zydelig?
Active ingredient: idelalisib
Inactive ingredients: microcrystalline
cellulose, hydroxypropyl cellulose, croscarmellose sodium, sodium starch
glycolate, and magnesium stearate.
The tablet coating contains polyethylene glycol, talc, polyvinyl alcohol,
titanium dioxide and FD&C Yellow #6 or Sunset Yellow (for the 100 mg
tablet) and red iron oxide (for the 150 mg tablet).
Manufactured and distributed by: Gilead Sciences, Inc. Foster City, CA 94404
©2016 Gilead Sciences, Inc. All rights reserved
For more information, call 1-800-445-3235 or go to www.Zydelig.com.
205858-GS-001-MG
|
PRINCIPAL DISPLAY PANEL - 100 mg Tablet Bottle Label
NDC 61958-1701-1
60 tablets
Zydelig®
(idelalisib) Tablets
100 mg
DISPENSER: Each time Zydelig® is dispensed
give the patient the attached Medication Guide.
PRINCIPAL DISPLAY PANEL - 150 mg Tablet Bottle Label
NDC 61958-1702-1
60 tablets
Zydelig®
(idelalisib) Tablets
150 mg
DISPENSER: Each time Zydelig® is dispensed
give the patient the attached Medication Guide.
|
Zydelig idelalisib tablet, film
coated
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:61958-1701
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
IDELALISIB (IDELALISIB)
|
IDELALISIB
|
100 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
HYDROXYPROPYL CELLULOSE (1200000 MW)
|
|
|
SODIUM STARCH GLYCOLATE TYPE A POTATO
|
|
|
CROSCARMELLOSE SODIUM
|
|
|
MAGNESIUM STEARATE
|
|
|
POLYVINYL ALCOHOL, UNSPECIFIED
|
|
|
TITANIUM DIOXIDE
|
|
|
POLYETHYLENE GLYCOL, UNSPECIFIED
|
|
|
TALC
|
|
|
FD&C YELLOW NO. 6
|
|
|
ALUMINUM OXIDE
|
|
|
|
Product
Characteristics
|
|
Color
|
orange
|
Score
|
no score
|
|
Shape
|
OVAL
|
Size
|
10mm
|
|
Flavor
|
|
Imprint Code
|
GSI;100
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:61958-1701-1
|
60 TABLET, FILM
COATED in 1 BOTTLE, PLASTIC
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA205858
|
07/23/2014
|
|
|
|
Zydelig idelalisib tablet, film
coated
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:61958-1702
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
IDELALISIB (IDELALISIB)
|
IDELALISIB
|
150 mg
|
|
|
Inactive Ingredients
|
|
Ingredient
Name
|
Strength
|
|
MICROCRYSTALLINE CELLULOSE
|
|
|
HYDROXYPROPYL CELLULOSE (1200000 MW)
|
|
|
SODIUM STARCH GLYCOLATE TYPE A POTATO
|
|
|
CROSCARMELLOSE SODIUM
|
|
|
MAGNESIUM STEARATE
|
|
|
POLYVINYL ALCOHOL, UNSPECIFIED
|
|
|
TITANIUM DIOXIDE
|
|
|
POLYETHYLENE GLYCOL, UNSPECIFIED
|
|
|
TALC
|
|
|
FERRIC OXIDE RED
|
|
|
|
Product
Characteristics
|
|
Color
|
pink
|
Score
|
no score
|
|
Shape
|
OVAL
|
Size
|
10mm
|
|
Flavor
|
|
Imprint Code
|
GSI;150
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:61958-1702-1
|
60 TABLET, FILM
COATED in 1 BOTTLE, PLASTIC
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
NDA
|
NDA205858
|
07/23/2014
|
|
|
|
Labeler - Gilead Sciences, Inc. (185049848)
|
Revised:
12/2017
Gilead Sciences, Inc.
