Glasdegib Maleate (Monograph)

Brand name: Daurismo
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Warning

May cause embryofetal death or severe birth defects. Embryotoxic, fetotoxic, and teratogenic in animals.
In women of childbearing potential, a pregnancy test must be obtained prior to treatment initiation. Advise such women to use effective methods of contraception during therapy and for at least 30 days after the last dose.
Potential risk of exposure through semen; advise male patients to use condoms during sexual encounters with a pregnant partner or a female partner of reproductive potential during therapy and for at least 30 days after the last dose.

[Web]

Introduction

Antineoplastic agent; a hedgehog signaling pathway inhibitor.

Uses for Glasdegib Maleate

Acute Myeloid Leukemia

Used in conjunction with low-dose cytarabine for treatment of newly diagnosed acute myeloid leukemia (AML) in patients ≥75 years of age or in those with comorbidities that preclude use of intensive induction chemotherapy; designated an orphan drug by FDA for treatment of AML.

Glasdegib Maleate Dosage and Administration

General

Pretreatment Screening

Verify pregnancy status in women of childbearing potential ≤7 days prior to initiating glasdegib.
Assess CBC, electrolytes, renal, and hepatic function prior to initiation of therapy.
Obtain creatine phosphokinase (CPK) levels prior to initiating therapy.
Monitor ECGs prior to therapy initiation.

Patient Monitoring

Assess ECG approximately 1 week after initiation, and then once monthly for the next 2 months. Monitor ECG more frequently in patients with congenital long QT syndrome, CHF, or electrolyte abnormalities and in those who are receiving drugs known to prolong the QT interval.
Monitor CBC, serum electrolyte concentrations, and renal and hepatic function at least once weekly for the first month of therapy. Monitor serum electrolyte concentrations and renal function monthly thereafter.
Monitor serum CK as clinically indicated (e.g., if musculoskeletal symptoms reported).

Administration

Oral Administration

Administer orally once daily without regard to food, at approximately the same time each day. Swallow tablets whole; do not split, crush, or chew.

If a dose is missed, advise the patient to take the dose as soon as it is remembered unless it is <12 hours until the next dose; if <12 hours remain before the next scheduled dose, skip the missed dose and take the next dose at the regularly scheduled time. Do not administer 2 doses within 12 hours.

If vomiting occurs after a dose is administered, take the next dose at the regularly scheduled time. Do not administer an additional dose to replace a dose that is vomited.

Dosage

Available as glasdegib maleate; dosage expressed in terms of glasdegib.

Adults

Acute Myeloid Leukemia

Oral

100 mg daily on days 1–28, in conjunction with cytarabine 20 mg sub-Q twice daily on days 1–10 of each 28-day cycle.

Continue therapy until disease progression or unacceptable toxicity occurs. Manufacturer recommends treatment for a minimum of 6 cycles to allow for clinical response.

Dosage Modification for Toxicity or Drug Interactions

Adverse effects may require temporary interruption and/or dosage reduction or discontinuance of glasdegib and/or cytarabine.

Prolongation of QT Interval

Oral

Recommended dosage modifications for QT-interval prolongation with glasdegib and low-dose cytarabine therapy are described in Table 1.

Table 1. Recommended Patient Monitoring and Dosage Modification for Prolongation of QT Interval.
Adverse Effect	Patient Monitoring	Dosage Modification
QT_c interval >480 to ≤500 msec on at least 2 separate ECGs	Assess electrolyte concentrations and correct as clinically indicated	Evaluate concomitant drugs known to prolong QT_c interval; adjust therapy as needed
	After QT_c interval returns to ≤480 msec, monitor ECG at least weekly for 2 weeks
QT_c interval >500 msec on at least 2 separate ECGs	Assess electrolyte concentrations and correct as clinically indicated	Interrupt glasdegib
	After QT_c interval returns to ≤480 msec, monitor ECG at least weekly for 2 weeks	After QT_c interval returns to within 30 msec of baseline or is ≤480 msec, resume glasdegib at reduced dosage of 50 mg once daily
		Evaluate concomitant drugs known to prolong QT_c interval; adjust therapy as needed
		Consider resuming glasdegib 100 mg once daily if alternative etiology for QT_c interval prolongation identified
QT_c interval prolongation occurring with life-threatening arrhythmias		Permanently discontinue glasdegib

Musculoskeletal Adverse Reactions

Oral

Musculoskeletal adverse effects with glasdegib and low-dose cytarabine therapy may require temporary interruption and/or dosage reduction or discontinuance of treatment as described in Table 2.

Table 2. Recommended Dosage Modifications for Musculoskeletal Adverse Reactions.1
Adverse Effect	Patient Monitoring	Dosage Modification
Grade 3 or CPK elevations 2.5-10 times upper limit of normal (ULN)	Obtain CPK and serum creatinine levels at least weekly until sign and symptom resolution	Interrupt glasdegib until symptoms reduce to mild or return to baseline Resume glasdegib at same dose level or at reduced dose of 50 mg If toxicity recurs, discontinue therapy
Grade 4 or CPK elevations >10 times ULN		Discontinue therapy

Hematologic Toxicity

Oral

Adverse effects related to hematologic toxicity with glasdegib and low-dose cytarabine therapy may require discontinuance of treatment as described in Table 3.

Table 3. Recommended Dosage Modification for Hematologic Toxicity.
Adverse Effect	Dosage Modification
Platelet count <10,000/mm³ for >42 days in absence of disease	Permanently discontinue glasdegib and low-dose cytarabine
ANC <500/mm³ for >42 days in absence of disease	Permanently discontinue glasdegib and low-dose cytarabine

Nonhematologic Toxicity

Oral

Adverse effects related to grade 3 or 4 nonhematologic toxicity with glasdegib and low-dose cytarabine therapy may require temporary interruption and/or dosage reduction or discontinuance of treatment as described in Table 4.

Table 4. Recommended Dosage Modification for Grade 3 or 4 Nonhematologic Toxicity.
Adverse Effect	Dosage Modification
Grade 3	Interrupt glasdegib and/or low-dose cytarabine until symptoms reduce to grade 1 or baseline
Grade 3	After resolution of toxicity, resume glasdegib at original dosage or at reduced dosage of 50 mg daily and resume low-dose cytarabine at original dosage or at reduced dosage of 15 mg or 10 mg twice daily
Grade 3	If grade 3 toxicity recurs, discontinue glasdegib and low-dose cytarabine
Grade 3	If toxicity is attributable to glasdegib only (e.g., dysgeusia, muscle spasm, alopecia), low-dose cytarabine may be continued
Grade 4	Permanently discontinue glasdegib and low-dose cytarabine

Concomitant Use with CYP3A4 Inducers

Oral

Avoid concomitant use with moderate or potent CYP3A4 inducers; if a moderate CYP3A4 inducer cannot be avoided, increase dosage of glasdegib. If the current glasdegib dosage is 100 mg once daily, increase to 200 mg once daily. If the current glasdegib dosage is 50 mg once daily, increase to 100 mg once daily. After the moderate CYP3A4 inducer has been discontinued for 7 days, resume the glasdegib dose taken prior to starting the moderate CYP3A4 inducer.

Special Populations

No specific dosage recommendations based on age, sex, race, or body weight.

Hepatic Impairment

No specific dosage recommendations for patients with hepatic impairment.

Renal Impairment

No specific dosage recommendations for patients with mild to severe renal impairment. Not studied in patients with end-stage renal disease (ESRD) requiring hemodialysis.

Geriatric Patients

No specific dosage recommendations for geriatric patients.

Cautions for Glasdegib Maleate

Contraindications

None.

Warnings/Precautions

Warnings

Embryo-Fetal Toxicity

May cause fetal harm, including embryofetal death or severe birth defects; teratogenicity, embryotoxicity, and fetotoxicity demonstrated in animals at exposures lower than those achieved in humans at the recommended daily dosage. (See Boxed Warning.)

Avoid pregnancy during therapy. Verify pregnancy status in women of childbearing potential ≤7 days prior to initiating glasdegib. Advise women of childbearing potential to use effective methods of contraception during treatment and for at least 30 days following drug discontinuance.

Because of the potential risk of exposure through semen, advise male patients (including those who have undergone vasectomy) to use a condom for each sexual encounter with a pregnant woman or woman of childbearing potential during and for at least 30 days after drug discontinuance. Advise men not to donate semen during and for at least 30 days after drug discontinuance.

Because of the potential risk of exposure in pregnant women through blood transfusion, advise patients not to donate blood or blood products during and for at least 30 days after drug discontinuance.

Report any drug exposure during pregnancy to the manufacturer by calling 800-438-1985.

Other Warnings and Precautions

Prolongation of QT Interval

QT_c prolongation and ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia, may occur. The prolongation appears to occur in a plasma concentration-dependent manner.

Monitor ECGs and serum electrolytes periodically and promptly manage any abnormalities. Monitor ECG more frequently in patients with congenital long QT syndrome, CHF, or electrolyte abnormalities and in those who are receiving drugs known to prolong the QT interval.

Musculoskeletal Adverse Reactions

Musculoskeletal adverse reactions, which may be accompanied by creatine phosphokinase (CPK) elevations, reported.

Obtain baseline CPK levels prior to initiating glasdegib and as clinically indicated (e.g., if muscle symptoms are reported). Obtain CPK and serum creatinine levels at least weekly in patients with musculoskeletal adverse reactions with concurrent CPK elevation >2.5 times ULN until resolution of clinical signs and symptoms. Depending on severity of symptoms, temporary dose interruption, dose reduction, or discontinuation of glasdegib may be required.

Specific Populations

Pregnancy

May cause fetal harm. (See Boxed Warning.)

Lactation

Not known whether distributed into human milk. Discontinue nursing during therapy and for at least 30 days after the last dose.

Effects on nursing infants or milk production unknown.

Females and Males of Reproductive Potential

Verify pregnancy status in women of reproductive potential within 7 days prior to initiation of therapy. Such patients should use effective contraceptive methods during therapy and for at least 30 days after the last dose.

Male patients, including those who have undergone vasectomy, should use effective contraceptive methods, including condoms, for each sexual encounter with pregnant women or women of reproductive potential while receiving glasdegib and for at least 30 days after the last dose. In addition, men should not donate semen while receiving glasdegib and for at least 30 days after the last dose.

Based on findings in animal studies, glasdegib 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

Safety and efficacy not established.

Geriatric Use

Most patients in the principal efficacy study were ≥65 years of age. Insufficient experience in patients <65 years of age to determine whether geriatric patients respond differently than younger adults.

Hepatic Impairment

Pharmacokinetics not substantially altered by mild hepatic impairment. Glasdegib pharmacokinetics altered in moderate and severe hepatic impairment.

No specific dosage recommendations for hepatic impairment.

Renal Impairment

Pharmacokinetics not substantially altered by mild renal impairment.

No dosage adjustment necessary in patients with renal impairment; however, monitor patients with severe renal impairment for adverse reactions.

Not studied in patients with ESRD requiring hemodialysis.

Common Adverse Effects

Adverse effects reported in ≥20% of patients: Anemia, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, rash.

Drug Interactions

Metabolized principally by CYP3A4, with minor contributions by CYP2C8 and UGT1A9.

Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro.

Does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A, and does not induce CYP1A2, 2B6, or 3A.

In vitro, inhibits P-gp, BCRP, multidrug and toxin extrusion transporters (MATE) 1, and MATE2K; does not inhibit organic anion transport protein (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, or organic cation transporter (OCT) 2.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased plasma concentrations of glasdegib and risk of adverse effects). Consider alternative therapy with drugs that are not potent CYP3A inhibitors; if concomitant use cannot be avoided, monitor for glasdegib adverse effects.

Moderate or potent CYP3A inducers: Possible pharmacokinetic interaction (decreased plasma concentrations of glasdegib and possible reduced efficacy). Avoid concomitant use. If concomitant use of a moderate CYP3A4 inducer cannot be avoided, increase glasdegib dosage from 100 mg to 200 mg once daily or from 50 mg to 100 mg once daily. May resume previous glasdegib dosage 7 days after discontinuance of the moderate CYP3A4 inducer.

Drugs that Prolong QT Interval

Potential pharmacologic interaction (increased risk of QT-interval prolongation). Consider alternative therapy with drugs that do not prolong the QT interval. If concomitant use cannot be avoided, monitor for QT-interval prolongation.

Specific Drugs

Drug	Interaction	Comments
Efavirenz	Decreased glasdegib peak concentrations and AUC expected	Avoid concomitant use; if concomitant use cannot be avoided, increase glasdegib dosage from 100 mg to 200 mg once daily or from 50 mg to 100 mg once daily Resume previous glasdegib dosage 7 days after efavirenz discontinued
Ketoconazole	Substantially increased glasdegib peak concentration and AUC	Avoid concomitant use; if concomitant use cannot be avoided, monitor for glasdegib adverse effects
Rabeprazole	Decreased glasdegib peak concentration, but no effect on glasdegib AUC; not considered clinically important
Rifampin	Substantially decreased glasdegib peak concentration and AUC	Avoid concomitant use

Glasdegib Maleate Pharmacokinetics

Absorption

Bioavailability

77%.

Systemic exposure and peak concentrations are dose-proportional over dosage range of 5–600 mg once daily.

Peak concentrations attained 1.3–1.8 hours after oral administration.

Steady-state concentrations achieved within 8 days with a median accumulation ratio of 1.2–2.5.

Food

Administration with high-fat, high-calorie meal reduces peak concentration and AUC; not considered clinically important.

Special Populations

Mild hepatic impairment (total bilirubin concentration between 1–1.5 times ULN or AST concentration exceeding ULN with total bilirubin concentration not exceeding ULN): No clinically important effects on glasdegib pharmacokinetics.

Moderate hepatic impairment (Child-Pugh class B): Glasdegib AUC increased by 11%.

Severe hepatic impairment (Child-Pugh class C): Glasdegib AUC decreased by 24%.

Mild renal impairment (Cl_cr 60–89 mL/minute): No clinically important effects on glasdegib pharmacokinetics.

Moderate (eGFR 30–59 mL/minute per 1.73 m²) or severe (eGFR 15–29 mL/minute per 1.73 m²) renal impairment: Glasdegib AUC increased 2.1-fold.

ESRD requiring hemodialysis: Not studied.

Distribution

Plasma Protein Binding

91%.

Elimination

Metabolism

Principally metabolized by CYP3A4 (60–80%), with minor contributions by CYP2C8 (2–20%) and UGT1A9.

Unchanged drug is the major component circulating in plasma; no active metabolites identified.

Elimination Route

Eliminated in urine (49%, 17% as unchanged drug) and feces (42%, 20% as unchanged drug).

Half-life

17.4 hours.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

Inhibits the hedgehog pathway by selectively binding to and inhibiting smoothened, a transmembrane protein involved in hedgehog signal transduction.
Hedgehog signaling pathway plays important role during embryonic organ and tissue development; also key regulator of maintenance of tissues and stem cells in adults.
Aberrant activation of the hedgehog pathway implicated in development of several malignancies, including hematologic malignancies.
Activation of smoothened results in activation of glioma (GLI) zinc finger transcription factors, which regulate gene transcription.
Glasdegib inhibits expression of activating transcription factor GLI1 via inhibition of smoothened.

Advice to Patients

Instruct patients to read the manufacturer's patient information.
Risk of fetal harm. Advise women of childbearing potential to use effective methods of contraception during glasdegib therapy and for at least 30 days after the last dose; importance of obtaining pregnancy tests prior to initiation of therapy. Advise female patients and female partners of men receiving glasdegib to contact clinician if pregnancy is suspected or confirmed.
Risk of exposure of pregnant women or women of childbearing potential to glasdegib through semen. Advise men receiving glasdegib (including those who have undergone vasectomy) to use a condom during sexual encounters with pregnant women or women of childbearing potential; these contraceptive measures are required during glasdegib therapy and for at least 30 days after the last dose. Advise men not to donate semen during glasdegib therapy and for at least 30 days after the last dose.
Advise patients to avoid donating blood or blood products while receiving glasdegib and for at least 30 days after the last dose.
Risk of serious adverse reactions in nursing infants. Advise women to avoid breast-feeding during glasdegib therapy and for at least 30 days after the last dose.
Advise men of reproductive potential that glasdegib may cause fertility problems and to discuss any concerns about fertility with their clinician.
Risk of musculoskeletal adverse effects. Advise patients to promptly report any new unexplained muscle pain, tenderness, or weakness occurring during therapy or that persists after discontinuation of therapy.
Risk of QT-interval prolongation. Inform patients of signs and symptoms that may be indicative of QT-interval prolongation; advise patients to contact a clinician immediately if they experience syncope, presyncope, dizziness, or cardiac palpitations.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of glasdegib is restricted. Contact manufacturer for additional information.