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Glasdegib

Class: Antineoplastic Agents
- Hedgehog Pathway Inhibitors
- Smoothened Inhibitors
Chemical Name: 1-[(2R,4R)-2-(1H-benzimidazol-2-yl)-1-methylpiperidin-4-yl]-3-(4-cyanophenyl)urea
Molecular Formula: C21H22N6O
CAS Number: 1095173-27-5
Brands: Daurismo

Medically reviewed by Drugs.com. Last updated on Aug 31, 2020.

Warning

Fetal/Neonatal Morbidity and Mortality

  • May cause embryofetal death or severe birth defects.1 Embryotoxic, fetotoxic, and teratogenic in animals.1

  • In women of childbearing potential, a pregnancy test must be obtained prior to treatment initiation.1 Advise such women to use effective methods of contraception during therapy and for at least 30 days after drug discontinuance.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • 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 drug discontinuance.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Introduction

Antineoplastic agent; a hedgehog signaling pathway inhibitor.1 2

Uses for Glasdegib

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;1 2 designated an orphan drug by FDA for treatment of AML.9

Glasdegib Dosage and Administration

General

  • Women of childbearing potential must be tested for pregnancy within 7 days prior to initiation of the drug.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Assess ECG at baseline, approximately 1 week after initiation, and then once monthly for the next 2 months.1 Some patients may require more frequent and ongoing ECG monitoring.1 (See Prolongation of QT Interval under Cautions.)

  • Monitor CBC, serum electrolyte concentrations, and renal and hepatic function at baseline and at least once weekly for the first month of therapy.1 Monitor serum electrolyte concentrations and renal function monthly thereafter.1 Promptly manage any abnormalities.1

  • Monitor serum CK at baseline and as clinically indicated (e.g., if musculoskeletal symptoms reported).1

Restricted Distribution

Obtain glasdegib through designated specialty pharmacies and distributors.10 Consult Pfizer Oncology Together at [Web] or call 877-744-5675 for specific availability information.10

Administration

Oral Administration

Administer orally once daily without regard to food, at approximately the same time each day.1 Swallow tablets whole; do not split, crush, or chew.1

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.1 Do not administer 2 doses within 12 hours.1

If vomiting occurs after a dose is administered, take the next dose at the regularly scheduled time.1 Do not administer an additional dose to replace a dose that is vomited.1

Dosage

Available as glasdegib maleate; dosage expressed in terms of glasdegib.1

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.1

Continue therapy until disease progression or unacceptable toxicity occurs.1 Manufacturer recommends treatment for a minimum of 6 cycles to allow for clinical response.1

Dosage Modification for Toxicity or Drug Interactions

Adverse effects may require temporary interruption and/or dosage reduction or discontinuance of glasdegib and/or cytarabine.1

Prolongation of QT Interval
Oral

Recommended dosage modifications for QT-interval prolongation with glasdegib and low-dose cytarabine therapy are described in Table 1.1 (Also see Prolongation of QT Interval under Cautions.)

Table 1. Recommended Patient Monitoring and Dosage Modification for Prolongation of QT Interval.

Adverse Effect

Patient Monitoring

Dosage Modification

QTc 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 QTc interval; adjust therapy as needed

After QTc interval returns to ≤480 msec, monitor ECG at least weekly for 2 weeks

QTc interval >500 msec on at least 2 separate ECGs

Assess electrolyte concentrations and correct as clinically indicated

Interrupt glasdegib

After QTc interval returns to ≤480 msec, monitor ECG at least weekly for 2 weeks

After QTc 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 QTc interval; adjust therapy as needed

Consider resuming glasdegib 100 mg once daily if alternative etiology for QTc interval prolongation identified

QTc interval prolongation occurring with life-threatening arrhythmias

Permanently discontinue glasdegib

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 2.1

Table 2. 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 3.1 6

Table 3. 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.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Special Populations

No specific dosage recommendations based on age, sex, race, or body weight.1

Hepatic Impairment

No specific dosage recommendations for patients with hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations for patients with mild to severe renal impairment.1 Not studied in patients with end-stage renal disease (ESRD) requiring hemodialysis.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations for geriatric patients.1 (See Geriatric Use under Cautions.)

Cautions for Glasdegib

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality.

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.1 (See Boxed Warning.)

Avoid pregnancy during therapy.1 Verify pregnancy status in women of childbearing potential ≤7 days prior to initiating glasdegib.1 Advise women of childbearing potential to use effective methods of contraception during treatment and for at least 30 days following drug discontinuance.1

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.1 Advise men not to donate semen during and for at least 30 days after drug discontinuance.1

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.1

Report any drug exposure during pregnancy to the manufacturer by calling 800-438-1985.1

Other Warnings and Precautions

Prolongation of QT Interval

QTc prolongation and ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia, may occur.1 The prolongation appears to occur in a plasma concentration-dependent manner.1

Monitor ECGs and serum electrolytes periodically and promptly manage any abnormalities.1 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.1 (See Interactions.)

Impairment of Male Fertility

Based on animal studies, may impair male fertility.1 Some effects on male fertility are potentially irreversible.1 (See Advice to Patients.)

Specific Populations

Pregnancy

May cause fetal harm.1 (See Boxed Warning and see Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into milk.1 Discontinue nursing during therapy and for at least 30 days after drug discontinuance.1

Effects on nursing infants or milk production unknown.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Most patients in the principal efficacy study were ≥65 years of age.1 Insufficient experience in patients <65 years of age to determine whether geriatric patients respond differently than younger adults.1

Hepatic Impairment

Pharmacokinetics not substantially altered by mild hepatic impairment.1 Glasdegib pharmacokinetics altered in moderate and severe hepatic impairment.1 (See Special Populations under Pharmacokinetics.)

No specific dosage recommendations for hepatic impairment.1

Renal Impairment

Pharmacokinetics not substantially altered by mild renal impairment.1 (See Special Populations under Pharmacokinetics.)

No dosage adjustment necessary in patients with renal impairment; however, monitor patients with severe renal impairment for adverse reactions.1

Not studied in patients with ESRD requiring hemodialysis.1

Common Adverse Effects

Anemia,1 2 fatigue,1 2 hemorrhage,1 febrile neutropenia,1 2 musculoskeletal pain,1 nausea,1 2 edema,1 2 thrombocytopenia,1 2 dyspnea,1 2 decreased appetite,1 2 dysgeusia,1 2 mucositis,1 constipation,1 2 rash,1 abdominal pain,1 pneumonia,1 2 renal insufficiency,1 pyrexia,1 2 diarrhea,1 2 vomiting,1 2 cough,1 2 dizziness,1 2 muscle spasm,1 2 decreased platelet count,1 decreased weight,1 atrial arrhythmia,1 chest pain,1 headache,1 hyponatremia,1 decreased leukocyte count,1 increased creatinine concentration,1 hyponatremia,1 hypomagnesemia,1 increased concentrations of aminotransferases (i.e., ALT, AST),1 increased bilirubin concentration,1 increased alkaline phosphatase concentration,1 hyperkalemia,1 increased CK concentration,1 hypokalemia.1

Interactions for Glasdegib

Metabolized principally by CYP3A4, with minor contributions by CYP2C8 and UGT1A9.1

Substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro.1

Does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A, and does not induce CYP1A2, 2B6, or 3A.1

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) 2.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased plasma concentrations of glasdegib and risk of adverse effects).1 Consider alternative therapy with drugs that are not potent CYP3A inhibitors; if concomitant use cannot be avoided, monitor for glasdegib adverse effects.1

Moderate or potent CYP3A inducers: Possible pharmacokinetic interaction (decreased plasma concentrations of glasdegib and possible reduced efficacy).1 Avoid concomitant use.1 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.1 May resume previous glasdegib dosage 7 days after discontinuance of the moderate CYP3A4 inducer.1

Drugs that Prolong QT Interval

Potential pharmacologic interaction (increased risk of QT-interval prolongation).1 Consider alternative therapy with drugs that do not prolong the QT interval.1 If concomitant use cannot be avoided, monitor for QT-interval prolongation.1 (See Prolongation of QT Interval under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Efavirenz

Decreased glasdegib peak concentrations and AUC expected1

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 daily1

Resume previous glasdegib dosage 7 days after efavirenz discontinued1

Ketoconazole

Substantially increased glasdegib peak concentration and AUC1 3

Avoid concomitant use; if concomitant use cannot be avoided, monitor for glasdegib adverse effects1

Rabeprazole

Decreased glasdegib peak concentration, but no effect on glasdegib AUC;1 7 not considered clinically important7

Rifampin

Substantially decreased glasdegib peak concentration and AUC1 3

Avoid concomitant use1

Glasdegib Pharmacokinetics

Absorption

Bioavailability

77%.1

Systemic exposure and peak concentrations are dose-proportional over dosage range of 5–600 mg once daily.1

Peak concentrations attained 1.3–1.8 hours after oral administration.1

Steady-state concentrations achieved within 8 days with a median accumulation ratio of 1.2–2.5.1

Food

Administration with high-fat, high-calorie meal reduces peak concentration and AUC; not considered clinically important.1 3 7

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.1

Moderate hepatic impairment (Child-Pugh class B): Glasdegib AUC increased by 11%.1

Severe hepatic impairment (Child-Pugh class C): Glasdegib AUC decreased by 24%.1

Mild renal impairment (Clcr 60–89 mL/minute): No clinically important effects on glasdegib pharmacokinetics.1

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.1 6

ESRD requiring hemodialysis: Not studied.1

Distribution

Plasma Protein Binding

91%.1

Elimination

Metabolism

Principally metabolized by CYP3A4 (60–80%), with minor contributions by CYP2C8 (2–20%) and UGT1A9.1 3

Unchanged drug is the major component circulating in plasma; no active metabolites identified.3

Elimination Route

Eliminated in urine (49%, 17% as unchanged drug) and feces (42%, 20% as unchanged drug).1 3

Half-life

17.4 hours.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Inhibits the hedgehog pathway by selectively binding to and inhibiting smoothened, a transmembrane protein involved in hedgehog signal transduction.1 2 8

  • Hedgehog signaling pathway plays important role during embryonic organ and tissue development; also key regulator of maintenance of tissues and stem cells in adults.1

  • Aberrant activation of the hedgehog pathway implicated in development of several malignancies, including hematologic malignancies.4 5 8

  • Activation of smoothened results in activation of glioma (GLI) zinc finger transcription factors, which regulate gene transcription.4 5 8

  • Glasdegib inhibits expression of activating transcription factor GLI1 via inhibition of smoothened.3

Advice to Patients

  • Importance of instructing patients to read the manufacturer's patient information.1

  • Risk of fetal harm.1 Necessity of advising women of childbearing potential to use effective methods of contraception during glasdegib therapy and for at least 30 days after discontinuance (see Fetal/Neonatal Morbidity and Mortality under Cautions); importance of obtaining pregnancy tests prior to initiation of therapy.1 Advise female patients and female partners of men receiving glasdegib to contact clinician if pregnancy is suspected or confirmed.1

  • Risk of exposure of pregnant women or women of childbearing potential to glasdegib through semen.1 Necessity of advising 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 discontinuance.1 Advise men not to donate semen during glasdegib therapy and for at least 30 days after discontinuance.1

  • Importance of advising patients to avoid donating blood or blood products while receiving glasdegib and for at least 30 days after discontinuance.1

  • Risk of serious adverse reactions in nursing infants.1 Importance of advising women to avoid breast-feeding during glasdegib therapy and for at least 30 days after discontinuance.1

  • Importance of advising men of reproductive potential that glasdegib may cause fertility problems and to discuss any concerns about fertility with their clinician.1

  • Risk of QT-interval prolongation.1 Importance of informing 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.1

  • 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.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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.10 (See Restricted Distribution under Dosage and Administration.)

Glasdegib Maleate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

25 mg (of glasdegib)

Daurismo

Pfizer

100 mg (of glasdegib)

Daurismo

Pfizer

AHFS DI Essentials™. © Copyright 2021, Selected Revisions August 31, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Pfizer Inc. Daurismo (glasdegib maleate) tablets prescribing information. New York, NY; 2020 Mar.

2. Cortes JE, Heidel FH, Hellmann A et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019; 33:379-389. http://www.ncbi.nlm.nih.gov/pubmed/30555165?dopt=AbstractPlus

3. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 210656Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210656Orig1s000ClinPharmR.pdf

4. Gupta S, Takebe N, Lorusso P. Targeting the Hedgehog pathway in cancer. Ther Adv Med Oncol. 2010; 2:237-50. http://www.ncbi.nlm.nih.gov/pubmed/21789137?dopt=AbstractPlus

5. Irvine DA, Copland M. Targeting hedgehog in hematologic malignancy. Blood. 2012; 119:2196-204. http://www.ncbi.nlm.nih.gov/pubmed/22223823?dopt=AbstractPlus

6. Pfizer Inc. New York, NY: Personal communication.

7. Shaik N, Hee B, Wei H et al. Evaluation of the effects of formulation, food, or a proton-pump inhibitor on the pharmacokinetics of glasdegib (PF-04449913) in healthy volunteers: a randomized phase I study. Cancer Chemother Pharmacol. 2019; 83:463-472. http://www.ncbi.nlm.nih.gov/pubmed/30536154?dopt=AbstractPlus

8. Terao T, Minami Y. Targeting Hedgehog (Hh) Pathway for the Acute Myeloid Leukemia Treatment. Cells. 2019; 8 http://www.ncbi.nlm.nih.gov/pubmed/30987263?dopt=AbstractPlus

9. Food and Drug Administration. FDA Application: Search orphan drug designations and approvals. Silver Spring, MD. From FDA website. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

10. Pfizer, Inc. Pfizer Oncology Together website. Accessed 2020 Apr 4. https://www.pfizeroncologytogether.com/hcp

Frequently asked questions