Glasdegib

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. DAURISMO is a hedgehog pathway inhibitor 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.

Glasdegib is an inhibitor of the Hedgehog pathway. Glasdegib binds to and inhibits Smoothened, a transmembrane 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 greater extent than glasdegib or low-dose cytarabine alone.

Recommended dosage: 100 mg orally once daily. Recommended Dosage and Schedule The recommended dosage of DAURISMO is 100 mg orally once daily on days 1 to 28 in combination with cytarabine 20 mg subcutaneously twice daily on days 1 to 10 of each 28-day cycle in the absence of unacceptable toxicity or loss of disease control. For patients without unacceptable toxicity, treat for a minimum of 6 cycles to allow time for clinical response. Administer DAURISMO with or without food. Do not split or crush DAURISMO tablets. Administer DAURISMO about the same time each day. If a dose of DAURISMO is vomited, do not administer a replacement dose, wait until the next scheduled dose is due. If a dose of DAURISMO is missed or not taken at the usual time, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose. Return to the normal schedule the following day.

None. None.

Boxed 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. • Blood Donation: Advise patients not to donate blood or blood products during treatment with DAURISMO and for at least 30 days after the last dose. • QTc Interval Prolongation: Monitor electrocardiograms and electrolytes. If QTc prolongation occurs, interrupt treatment with DAURISMO. • Musculoskeletal Adverse Reactions: Obtain creatine phosphokinase (CPK) and serum creatinine levels prior to initiating DAURISMO and as indicated clinically thereafter.

The following clinically-significant adverse reactions are described elsewhere in the labeling: • QTc Interval Prolongation • Musculoskeletal Adverse Reactions Most common adverse reactions (incidence ≥20%) are anemia, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash.

Table 5. 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. Strong and Moderate CYP3A Inducers Clinical Impact Co-administration of DAURISMO with strong and moderate CYP3A inducers decreased glasdegib plasma concentrations. • Decreased glasdegib concentrations may reduce efficacy. Prevention or Management • Avoid co-administration of DAURISMO with strong and moderate CYP3A4 inducers.

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F).