Glasdegib

Indications

Glasdegib is used for: Acute Myeloid Leukemia

Adult Dose

Acute Myeloid Leukemia Indicated, in combination with low-dose cytarabine, for newly diagnosed acute myeloid leukemia (AML) in adults aged ?75 years or who have comorbidities that preclude use of intensive induction chemotherapy 100 mg PO qDay on days 1-28 of each 28-day cycle; administer in combination with cytarabine 20 mg SC BID on days 1-10 For patients without unacceptable toxicity, treat for a minimum of 6 cycles to allow time for clinical response

Child Dose

Renal Dose

Administration

Administer with or without food Swallow tablet whole; do not split or crush Administer at about the same time each day

Contra Indications

Precautions

Based on mechanism of action and findings from animal studies, can cause embryo-fetal death or severe birth defects when administered to pregnant women Development of QTc prolongation and ventricular arrhythmias reported, including ventricular fibrillation and ventricular tachycardia; more frequent ECG monitoring advised in patients with congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval

Pregnancy-Lactation

Pregnancy Based on its mechanism of action and findings in animal embryo-fetal developmental toxicity studies, glasdegib can cause fetal harm when administered to pregnant women Animal studies Exposure 3-4 times that of humans: Resulted in embryo-fetal lethality (eg, increased postimplantation loss and decreased numbers of live fetuses) in rats and rabbits Exposure 0.6 times that of humans: 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 Infertility Males: Based on findings in repeat-dose animal toxicity studies in rats, may impair fertility in males of reproductive potential; some effects on male reproductive organs did not recover Contraception Females of reproductive potential: Use effective contraception during treatment and for at least 30 days after last dose Do not donate blood during treatment and for at least 30 days after last dose Males Unknown if 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 for at least 30 days after last dose Advise males to not donate sperm or blood during treatment and for at least 30 days after last dose Lactation No data are available on the presence in human milk, effects on the breastfed child, or effect on milk production Advise women not to breastfeed or provide breast milk to infants or children during treatment and for at least 30 days after last dose

Interactions

Strong CYP3A inhibitors Coadministration may increase glasdegib plasma concentrations and increase risk for QT prolongation Strong CYP3A inducers Coadministration may decrease glasdegib plasma concentrations, thereby reducing efficacy Prolonged QTc Associated with concentration-dependent QTc prolongation Avoid coadministration with QTc prolonging drugs If unavoidable, monitor for increased risk of QTc interval prolongation

Adverse Effects

Side effects of Glasdegib : >10% (All Grades Glasdegib with Cytarabine) Increased creatinine (96%) Hyponatremia (11-54%) Anemia (43%) Hemorrhage (36%) Fatigue (36%) Hypomagnesemia (33%) Febrile neutropenia (31%) Thrombocytopenia (30%) Edema (30%) Musculoskeletal pain (30%) Nausea (29%) Increased AST (28%) Increased blood bilirubin (25%) Increased ALT (24%) Increased alkaline phosphatase (23%) Mucositis (21%) Decreased appetite (21%) Dysgeusia (21%) Constipation (20%) Rash (20%) Abdominal pain (19%) Pneumonia (19%) Renal insufficiency (19%) Pyrexia (18%) Diarrhea (18%) Vomiting (18%) Dizziness (18%) Hyperkalemia (16%) Increased CPK (16%) Muscle spasm (15%) Decreased platelet count (15%) Hypokalemia (15%) Weight decreased (13%) Atrial arrhythmia (13%) Chest pain (12%) Headache (12%)

Mechanism of Action

Inhibits the smoothen (SMO) receptor, a transmembrane protein involved in hedgehog (Hh) signal transduction, thereby disrupting the Hh pathway SMO inhibition of Hh signaling impacts tumor biology by disrupting the regulation of cancer stem cell survival; this may inhibit development of drug resistance and prevent relapse