ASH Clinical News ACN_5.4_Full Issue_web | Page 5

Cough includes cough and productive cough.
Dysgeusia includes dysgeusia and ageusia.
o.
Rash includes rash, pruritus, erythema, skin ulcer, rash maculo-papular, and rash pruritic.
p.
Pneumonia includes pneumonia, pneumonia aspiration, and lung infection.
q.
Atrial arrhythmia includes atrial fibrillation, bradycardia, tachycardia, and sinus tachycardia.
r.
Renal insufficiency includes acute kidney injury, blood creatinine increased, oliguria, and renal failure.
m.
n.
The adverse reactions muscle spasms (4 in 12 patients) and decreased appetite (2 in 10 patients) worsened
(i.e. progressed from Grades ≤ 2 to Grade 3 or higher) after the first 90 days of therapy in BRIGHT AML 1003.
Additional clinically-significant adverse reactions occurring in < 10% of patients treated with DAURISMO and
low-dose cytarabine in BRIGHT AML 1003 include:
• Dental disorders: loose tooth and toothache
• Skin and subcutaneous tissue disorders: alopecia
• Cardiac disorders: QT interval prolonged
Changes in selected post-baseline laboratory values that were observed in patients with newly-diagnosed AML
and other conditions for which DAURISMO is not indicated in the clinical trial are shown in the following table.
Selected Laboratory Abnormalities (≥ 15%) a Within the First 90 Days of Therapy in BRIGHT AML 1003
DAURISMO with
Low-Dose Cytarabine
Low-Dose Cytarabine
N All Grades
% Grade 3
or 4*
% N All Grades
% Grade 3
or 4*
%
Creatinine increased 81 96 1 40 80 5
Hyponatremia 81 54 7 39 41 8
Hypomagnesemia 81 33 0 39 23 0
AST increased 80 28 1 40 23 0
Blood bilirubin increased 80 25 4 39 33 3
ALT increased 80 24 0 40 28 3
Alkaline phosphatase
increased 80 23 0 40 28 3
Hyperkalemia 81 16 1 40 8 3
CPK increased 38 16 0 17 6 0
Hypokalemia 81 15 0 40 23 0
Laboratory Abnormality
Abbreviations: N = number of patients; AST = aspartate aminotransferase; ALT = alanine aminotransferase; CPK = creatinine phosphokinase.
BRIGHT AML 1003 used National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
*Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.
a.
Maximum severity based on the number of patients with available on-study laboratory data.
The following laboratory abnormalities worsened (i.e. progressed from Grades ≤ 2 to Grade 3 or higher)
after the first 90 days of therapy in BRIGHT AML 1003:
• hypophosphatemia (8 in 38 patients), creatinine increased (2 in 39 patients), and ALT increased (2 in
40 patients).
DRUG INTERACTIONS
Drug Interactions with DAURISMO
Strong CYP3A Inhibitors
Clinical Impact • Co-administration of DAURISMO with strong CYP3A inhibitors
increased glasdegib plasma concentrations.
• Increased glasdegib concentrations may increase the risk of adverse
reactions including QTc interval prolongation.
Prevention or
Management • Consider alternative therapies that are not strong CYP3A4 inhibitors
during treatment with DAURISMO.
• Monitor patients for increased risk of adverse reactions including QTc
interval prolongation.
USE IN SPECIFIC POPULATIONS
Pregnancy: Risk Summary: Based on its mechanism of action and findings in animal embryo-fetal
developmental toxicity studies, DAURISMO can cause fetal harm when administered to a pregnant woman.
There are no clinical data on the use of DAURISMO in pregnant women to inform of a drug-associated risk
of major birth defects and miscarriage. DAURISMO is not recommended for use during pregnancy. Conduct
pregnancy testing in female patients of reproductive potential prior to initiating treatment with DAURISMO.
Report pregnancy exposures to Pfizer at 1-800-438-1985. In animal embryo-fetal developmental toxicity
studies, repeat-dose oral administration of DAURISMO during organogenesis at maternal exposures that
were less than the human exposure at the recommended dose resulted in embryotoxicity, fetotoxicity and
teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus. The estimated
background risk of major birth defects and miscarriage for the indicated population are unknown. Adverse
outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the
U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically
recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data: Animal Data: In embryo-fetal
developmental toxicity studies, glasdegib was orally administered to pregnant rats and rabbits at doses
up to 100 mg/kg/day during the period of organogenesis. Glasdegib resulted in embryo-fetal lethality
(e.g., increased postimplantation loss and decreased numbers of live fetuses) in rats and rabbits at
50 mg/kg/day and 5 mg/kg/day, respectively, at maternal exposures approximately 4-times and 3-times
the human exposure at the recommended dose [based on C max (rat) and AUC (rabbit)]. Doses of ≥ 10 mg/kg
in rat [approximately 0.6-times the human exposure (C max ) at the recommended dose] and ≥ 5 mg/kg
in rabbit resulted in fetal developmental abnormalities and malformations consisting of craniofacial
malformations, malformed limbs, paws/digits, trunk and tail, dilation of brain, malpositioned/malformed
eyes, misshapen head, small tongue, absent palate, teeth and viscera, diaphragmatic hernia, edema, heart
defects, rib and vertebral abnormalities, malformed or absent structures in the appendicular skeleton.
Lactation: Risk Summary: There are no data on the presence of glasdegib or its active metabolites in human
milk, the effects of the drug on the breastfed child, or its effect on milk production. Because of the potential
for serious adverse reactions in a breastfed child from DAURISMO, advise women who are taking DAURISMO
not to breastfeed or provide breast milk to infants or children during treatment with DAURISMO and for at
least 30 days after the last dose.
Females and Males of Reproductive Potential: DAURISMO can cause fetal harm when administered to a
pregnant woman. Pregnancy Testing: Conduct pregnancy testing in females of reproductive potential within
7 days prior to initiating therapy with DAURISMO. Contraception: Females: Advise females of reproductive
potential to use effective contraception during treatment with DAURISMO and at least 30 days after the last
dose. Males: It is not known if glasdegib is present in semen. Advise males of the potential risk of exposure
through semen and to use effective contraception, including a condom, even after a 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. Advise males to not donate semen during treatment
with DAURISMO for at least 30 days after the last dose. Infertility: Males: Based on findings in repeat-
dose animal toxicity studies in rats, DAURISMO may impair fertility in males of reproductive potential.
Some effects on male reproductive organs did not recover. Men should seek advice on effective fertility
preservation before treatment.
Pediatric Use: The safety and effectiveness of DAURISMO have not been established in pediatric patients.
In repeat-dose toxicity studies in rats, oral administration of DAURISMO resulted in adverse changes in
growing bone, teeth, and testis. Effects on bone consisted of partial to complete closure of the epiphyseal
plate. Effects in growing incisor teeth included degeneration/necrosis of ameloblasts, and complete
tooth loss with oral ulceration. Reproductive tissue toxicity was evidenced by testicular degeneration
and hypospermatogenesis. These effects in bone, teeth and testis were observed after administration of
DAURISMO for 26 weeks at greater than or equal to 50 mg/kg/day corresponding to approximately 6.6-times
the steady state AUC in patients at the recommended human dose.
Geriatric Use: Of the total number of subjects in clinical studies of DAURISMO with low-dose cytarabine
(N=88), 98% of the patients were age 65 years or older and 60% of the patients were age 75 years or older.
There were insufficient patients younger than age 65 years to determine differences in adverse reactions
reported from patients older than 65.
Rx only
This brief summary is based on DAURISMO Prescribing Information LAB-1284-1.0, revised November 2018,
which can be found at DAURISMO.com.
Strong CYP3A Inducers
Clinical Impact Co-administration of DAURISMO with strong CYP3A inducers decreased
glasdegib plasma concentrations.
Prevention or
Management Avoid co-administration of DAURISMO with strong CYP3A4 inducers.
QTc Prolonging Drugs
Clinical Impact Co-administration of DAURISMO with QTc prolonging drugs may
increase the risk of QTc interval prolongation.
Prevention or
Management • Avoid co-administration of QTc prolonging drugs with DAURISMO or
replace with alternative therapies.
• If co-administration of a QTc prolonging drug is unavoidable, monitor
patients for increased risk of QTc interval prolongation.
© 2018 Pfizer Inc.
All rights reserved.
Printed in USA/December 2018