may impair fertility in males ofreproductive potential. Some effects on male reproductive organs did not recover [see Nonclinical Toxicology(13.1)].
Men should seek advice on effective fertility preservation before treatment.
8.4 Pediatric Use
The safety and effectiveness of DAURISMO have not been established in pediatric patients. In repeat-dosetoxicity 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 effectsin bone, teeth and testis were observed after administration of DAURISMO for 26 weeks at greater than orequal to 50 mg/kg/day corresponding to approximately 6.6-times the steady state AUC in patients at the
recommended human dose.
8.5 Geriatric Use
Of the total number of subjects in clinical studies of DAURISMO with low-dose cytarabine (N=88), 98% of thepatients were age 65 years or older and 60% of the patients were age 75 years or older.
There were insufficientpatients younger than age 65 years to determine differences in adverse reactions reported from patients olderthan 65.
10 OVERDOSAGE
There is no specific antidote for DAURISMO. Management of DAURISMO overdose should includesymptomatic treatment and ECG monitoring.
Glasdegib has been administered in clinical studies up to a dose of 640 mg/day. At the highest dosage theadverse events reported were nausea, vomiting, dehydration, fatigue and dizziness.
11 DESCRIPTION
DAURISMO (glasdegib) is a potent small molecule inhibitor of Smoothened (SMO) for oral use. It isformulated with the maleate salt of glasdegib. The molecular formula for glasdegib maleate is C25H26N6O5.
Themolecular weight for glasdegib maleate is 490.51 Daltons. The chemical name of glasdegib maleate is1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl)urea maleate.
Themolecular structure is shown below:
N
HN
N
H
N
Me
N
H
O CN
CO2H
CO2H
Glasdegib maleate is a white to pale colored powder with pKa values of 1.7 and 6.1. The aqueous solubility ofglasdegib maleate is 1.7 mg/mL.
DAURISMO (glasdegib) is supplied as a film-coated tablet for oral use containing either 100 mg glasdegib(equivalent to 131.1 mg glasdegib maleate) or 25 mg of glasdegib (equivalent to 32.8 mg glasdegib maleate)together with microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and
magnesium stearate as inactive ingredients in the tablet. The film-coating consists of Opadry II® Beige(33G170003) and Opadry II® Yellow (33G120011) containing: hypromellose, titanium dioxide, lactosemonohydrate, macrogol, triacetin, iron oxide yellow, and iron oxide red.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Glasdegib is an inhibitor of the Hedgehog pathway. Glasdegib binds to and inhibits Smoothened, atransmembrane protein involved in hedgehog signal transduction.
In a murine xenotransplant model of human AML, glasdegib in combination with low-dose cytarabine,inhibited increases in tumor size and reduced the percentage of CD45+/CD33+ blasts in the marrow to a greaterextent than glasdegi |
