DAURISMO TM (glasdegib) tablets, for oral use
Initial U.S. Approval: 2018
Brief Summary of Prescribing Information
WARNING: EMBRYO-FETAL TOXICITY
DAURISMO can cause embryo-fetal death or severe birth defects when administered to a pregnant
woman. DAURISMO is embryotoxic, fetotoxic, and teratogenic in animals.
Conduct pregnancy testing in females of reproductive potential prior to initiation of DAURISMO
treatment. Advise females of reproductive potential to use effective contraception during
treatment with DAURISMO and for at least 30 days after the last dose.
Advise males of the potential risk of DAURISMO exposure through semen and to use condoms with
a pregnant partner or a female partner of reproductive potential during treatment with DAURISMO
and for at least 30 days after the last dose to avoid potential drug exposure.
INDICATIONS AND USAGE
DAURISMO is indicated, in combination with low-dose cytarabine, for the treatment of newly-diagnosed
acute myeloid leukemia (AML) in adult patients who are ≥75 years old or who have comorbidities that
preclude use of intensive induction chemotherapy.
Limitation of Use: DAURISMO has not been studied in patients with the comorbidities of severe renal
impairment or moderate-to-severe hepatic impairment.
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal embryo-fetal
developmental toxicity studies, DAURISMO can cause embryo-fetal death or severe birth defects when
administered to a pregnant woman. There are no clinical data on the use of DAURISMO in pregnant women.
In animal embryo-fetal developmental toxicity studies, glasdegib caused embryotoxicity, fetotoxicity and
teratogenicity at maternal exposures that were less than the human exposure at the recommended human
dose of 100 mg. Advise pregnant women of the potential risk to the fetus. Females of Reproductive Potential:
DAURISMO is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of
reproductive potential prior to initiating DAURISMO treatment. Advise females of reproductive potential to
use effective contraception during treatment with DAURISMO and for at least 30 days after the last dose.
Advise women not to breastfeed during treatment with DAURISMO and for at least 30 days after the last
dose. Males: Advise male patients with female partners of the potential risk of exposure through semen
and to use effective contraception, including a condom, even after vasectomy, to avoid drug exposure to a
pregnant partner or a female partner of reproductive potential during treatment with DAURISMO and for
at least 30 days after the last dose. Blood Donation: Advise patients not to donate blood or blood products
while taking DAURISMO and for at least 30 days after the last dose of DAURISMO because their blood or blood
products might be given to a female of reproductive potential.
QTc Interval Prolongation: Patients treated with DAURISMO can develop QTc prolongation and ventricular
arrhythmias, including ventricular fibrillation and ventricular tachycardia. Of the 98 evaluable patients
treated with DAURISMO 100 mg in combination with low-dose cytarabine in the clinical trial, 5% were found
to have a QTc interval greater than 500 ms and 4% of patients had an increase from baseline QTc greater than
60 ms. The clinical trial excluded patients with baseline QTc of greater than 470 ms or with a history of long
QT syndrome or uncontrolled cardiovascular disease.
Monitor electrocardiograms (ECGs) and electrolytes. Concomitant use of DAURISMO with drugs known to
prolong the QTc interval and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. In patients
with congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or those who are
taking medications known to prolong the QTc interval, more frequent ECG monitoring is recommended.
Interrupt DAURISMO if QTc increases to greater than 500 ms. Discontinue DAURISMO permanently for patients
who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.
ADVERSE REACTIONS
The following clinically significant adverse reaction is described elsewhere in the labeling:
• QT Interval Prolongation
Clinical Trials 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.
The safety profile of DAURISMO is based on experience in the BRIGHT AML 1003 study for 111 adults with
newly-diagnosed AML and 14 adults with other conditions for which DAURISMO is not indicated. Patients
were treated with DAURISMO 100 mg daily in combination with low-dose cytarabine (N=84) or low-dose
cytarabine alone (N=41). The median duration of treatment in the DAURISMO with low-dose cytarabine arm
was 83 days (range 3 to 972 days), and the median duration of treatment in the low-dose cytarabine alone
arm was 47 days (range 6 to 239 days). The median exposure to DAURISMO in the DAURISMO with low-dose
cytarabine arm was 76 days (range 3 to 954 days). Thirty-two patients (38%) were treated with DAURISMO
with low-dose cytarabine for at least 6 months and 14 patients (17%) were treated for at least 1 year.
Serious adverse reactions were reported in 79% of patients treated in the DAURISMO with low-dose
cytarabine arm. The most common (≥5%) serious adverse reactions in patients receiving DAURISMO with
low-dose cytarabine were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%),
and sepsis (7%).
Dose reductions associated with adverse reactions were reported in 26% of patients treated with DAURISMO
with low-dose cytarabine, and the most common reasons (≥2%) for dose reductions due to adverse
reactions were muscle spasms (5%), fatigue (4%), febrile neutropenia (4%), anemia (2%), thrombocytopenia
(2%), and ECG QT prolonged (2%). Adverse reactions leading to permanent discontinuation were reported
in 36% of patients treated with DAURISMO with low-dose cytarabine, and the most common (≥2%) reasons
for permanent discontinuation were pneumonia (6%), febrile neutropenia (4%), sepsis (4%), sudden death
(2%), myocardial infarction (2%), nausea (2%), and renal insufficiency (2%).
Adverse reactions reported in the first 90 days of therapy on the BRIGHT AML 1003 study are shown in the
following table.
Adverse Reactions Occurring in ≥ 10% of Patients a,b Within the First 90 Days of Therapy in
BRIGHT AML 1003
Body System
Adverse Reactions
DAURISMO With
Low-Dose Cytarabine
N=84
Low-Dose Cytarabine
N=41
All Grades Grade ≥ 3 All Grades Grade ≥ 3
%
%
%
%
Blood and lymphatic
system disorder Anemia
Hemorrhage c
Febrile neutropenia
Thrombocytopenia 43
36
31
30 41
6
31
30 42
42
22
27 37
12
22
24
General disorders
and administration
site conditions Fatigue d
Edema e
Mucositis f
Pyrexia
Chest pain g 36
30
21
18
12 14
0
1
1
1 32
20
12
22
2 7
2
0
2
0
Musculoskeletal and
Musculoskeletal pain h
connective tissue disorders Muscle spasm i 30
15 2
0 17
5 2
0
Gastrointestinal disorders Nausea
Constipation
Abdominal pain j
Diarrhea k
Vomiting 29
20
19
18
18 1
1
0
4
2 12
12
12
22
10 2
0
0
0
2
Respiratory thoracic and
mediastinal disorders Dyspnea l
Cough m 23
18 11
0 24
15 7
2
Metabolism and
nutrition disorders Decrease appetite 21 1 7 2
Nervous system disorders Dysgeusia n
Dizziness
Headache 21
18
12 0
1
0 2
7
10 0
0
2
Skin and subcutaneous
tissue disorders 20 2 7 2
Infection and infestations Pneumonia p 19 15 24 22
Investigations Hyponatremia
Platelet count decreased
Weight decreased
White blood cell count
decreased 11
15
13
11 6
15
0
11 0
10
2
5 0
10
0
2
Cardiac disorders Atrial arrhythmia q 13 4 7 2
Renal and urinary
disorders Renal insufficiency 19 5 10 0
Rash o
r
Abbreviations: N = number of patients.
Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 19.1.
BRIGHT AML 1003 used National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Adverse reactions include events that commenced within 28 days after the last treatment dose.
a.
Adverse reactions with ≥10% incidence in the DAURISMO with low-dose cytarabine arm or the low-dose cytarabine arm are included.
b.
No Grade 5 events in the DAURISMO with low-dose cytarabine or low-dose cytarabine alone arm.
c.
Hemorrhage includes petechiae, epistaxis, hematoma, contusion, rectal hemorrhage, anal hemorrhage, ecchymosis, gingival bleeding,
hematuria, mouth hemorrhage, purpura, cerebral hemorrhage, eye contusion, eye hemorrhage, gastric hemorrhage, gastrointestinal
hemorrhage, hematemesis, hemoptysis, hemorrhage, implant site hematoma, injection site bruising, retroperitoneal hematoma,
thrombotic thrombocytopenic purpura, tracheal hemorrhage, conjunctival hemorrhage, disseminated intravascular coagulation, eyelid
hematoma, hematochezia, hemorrhage intracranial, hemorrhoidal hemorrhage, lower gastrointestinal hemorrhage, retinal hemorrhage,
and subdural hematoma.
d.
Fatigue includes asthenia and fatigue.
e.
Edema includes edema peripheral, edema, fluid overload, fluid retention, and swelling face.
f.
Mucositis includes mucosal inflammation, oropharyngeal pain, stomatitis, anal ulcer, gingival pain, laryngeal inflammation, esophagitis,
oral pain, aphthous ulcer, mouth ulceration, and pharyngeal inflammation.
g.
Chest pain includes chest pain and non-cardiac chest pain.
h.
Musculoskeletal pain includes pain in extremity, arthralgia, back pain, myalgia, musculoskeletal pain, musculoskeletal chest pain, neck
pain, and bone pain.
i.
Muscle spasms includes muscle spasms and muscle tightness.
j.
Abdominal pain includes abdominal pain, abdominal pain upper, and abdominal pain lower.
k.
Diarrhea includes diarrhea, colitis, and gastroenteritis.
l.
Dyspnea includes dyspnea, hypoxia, bronchospasm, and respiratory failure.