Glasdegib, a hedgehog signaling pathway inhibitor, is an antineoplastic agent.1, 2
Glasdegib maleate is used in conjunction with low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients 75 years of age or older or in those who have comorbidities that preclude use of intensive induction chemotherapy.1, 2 Glasdegib has been designated an orphan drug by the FDA for the treatment of this cancer.9
The current indication for glasdegib in the treatment of AML is based principally on the results of a multicenter, randomized, open-label phase 2 study (BRIGHT AML 1003) in 115 adults with newly diagnosed AML.1, 2 In this study, patients were 55 years of age or older and were not considered candidates for intensive chemotherapy, defined as meeting at least one of the following criteria at baseline: 75 years of age or older, Eastern Cooperative Oncology Group (ECOG) performance status of 2, serum creatinine concentrations exceeding 1.3 mg/dL, or the presence of severe cardiac disease (e.g., left ventricular ejection fraction [LVEF] less than 45%).1, 2 Patients were randomized in a 2:1 ratio to receive glasdegib 100 mg daily in conjunction with low-dose cytarabine (20 mg subcutaneously twice daily on days 1-10) or low-dose cytarabine alone in 28-day cycles until disease progression or unacceptable toxicity occurred, or the patient withdrew from the study.1, 2 The primary efficacy end point was overall survival.1
The median age of patients enrolled in the study was 76 years (range: 58-92 years); 71% were male and 98% were white.1 Approximately 50% of patients had an ECOG performance status of 0 or 1 and 50% had an ECOG performance status of 2.1 Over half of the patients had baseline severe cardiac disease.1 Patients also were stratified by cytogenetic risk; in the glasdegib plus low-dose cytarabine or low-dose cytarabine alone treatment groups, 62 or 55% of patients, respectively, were considered good/intermediate risk and 38 or 45%, respectively, were considered poor risk.1, 2
At a median follow-up of approximately 20 months, the median overall survival was substantially longer in patients receiving glasdegib in conjunction with low-dose cytarabine compared with those receiving low-dose cytarabine alone (8.3 versus 4.3 months; hazard ratio: 0.46).1, 2 Improvement in overall survival with glasdegib plus low-dose cytarabine was consistent across cytogenetic risk subgroups.1 Complete response was achieved in 18.2% of patients receiving both drugs compared with 2.6% of patients receiving low-dose cytarabine alone.1
In 2020, the American Society of Hematology (ASH) published guidelines for treating newly diagnosed AML in older adults.100 The ASH guideline panel recommends offering antileukemic therapy to older adults with newly diagnosed AML over best supportive care.100 For those older adults considered appropropriate for antileukemic therapy but not for intensive therapy, the ASH guideline panel suggests using monotherapy with a hypomethylating agent (azacitidine or decitabine) or low-dose cytarabine over combination therapy including one of these medications with other agents.100 However, if combination therapy is chosen, the panel noted that glasdegib plus low-dose cytarabine may be an option.100
Glasdegib is administered orally once daily at approximately the same time each day, without regard to food.1 The tablets should be swallowed whole and should not be split, crushed, or chewed.1
If a dose is missed, the dose should be taken as soon as it is remembered unless it is less than 12 hours until the next dose; if less than 12 hours remain before the next scheduled dose, the missed dose should be skipped and the next dose taken at the regularly scheduled time.1 Two doses should not be administered within 12 hours.1
If vomiting occurs after a dose is administered, the next dose should be taken at the regularly scheduled time.1 An additional dose should not be administered to replace a dose that is vomited.1
Dosage of glasdegib maleate is expressed in terms of glasdegib.1
For the treatment of newly diagnosed acute myeloid leukemia (AML), the recommended adult dosage of glasdegib is 100 mg daily on days 1-28 in conjunction with cytarabine 20 mg subcutaneously twice daily on days 1-10 of each 28-day cycle.1 Treatment should be continued until disease progression or unacceptable toxicity occurs.1 The manufacturer recommends treatment for a minimum of 6 cycles to allow for clinical response.1
Dosage Modification for Toxicity or Drug Interactions
In the principal efficacy study evaluating glasdegib in conjunction with low-dose cytarabine, dosage modification or discontinuance of therapy resulting from adverse effects occurred in 26 or 36%, respectively, of patients receiving the regimen.1, 2
In the principal efficacy study, if the toxicity was attributable to low-dose cytarabine only, low-dose cytarabine was interrupted or the dosage reduced while glasdegib was continued at the same dosage.6 If the toxicity could not be attributed to either drug, the study protocol recommended initial dosage reduction of glasdegib followed by dosage reduction of cytarabine as clinically indicated.6
Adverse effects related to QT-interval prolongation with glasdegib and low-dose cytarabine therapy may require temporary interruption and/or dosage reduction or discontinuance of treatment as described in Table 1.1
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 with life-threatening arrhythmias | Permanently discontinue glasdegib |
Muculoskeletal Adverse Reactions
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 2.1
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 |
Adverse effects related to hematologic toxicity with glasdegib and low-dose cytarabine therapy may require discontinuance of treatment as described in Table 3.1
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 |
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 4.1, 6
Adverse Effect | Dosage Modification |
|---|---|
Grade 3 | Interrupt glasdegib and/or low-dose cytarabine until symptoms reduce to grade 1 or baseline |
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 | |
If grade 3 toxicity recurs , discontinue glasdegib and low-dose cytarabine | |
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 Cytochrome P-450 (CYP) 3A4 Inducers
Concomitant use of glasdegib and moderate and strong inducers of CYP3A4 should be avoided; if concomitant use with a moderate CYP3A4 inducer cannot be avoided, increase the dosage of glasdegib.1 If the current glasdegib dosage is 100 mg once daily, increase to 200 mg once daily.1 If the current glasdegib dosage is 50 mg once daily, increase to 100 mg once daily.1 After the moderate CYP3A4 inducer has been discontinued for 7 days, resume the glasdegib dose taken prior to starting the moderate CYP3A4 inducer.1
The manufacturer makes no specific dosage recommendations based on age, sex, race, body weight, or the presence of hepatic impairment.1
No dosage adjustment is necessary in patients with mild to severe renal impairment.1
Based on its mechanism of action and data from animal studies, glasdegib may cause fetal harm, including embryofetal death or severe birth defects, if administered to pregnant women.1 There are no clinical data on the use of glasdegib in pregnant women.1 Teratogenicity, embryotoxicity, and fetotoxicity have been demonstrated in animals at exposures lower than those achieved in humans at the recommended daily dosage.1 Fetal malformations in animals have included craniofacial anomalies, malformed limbs, brain dilation, malpositioned eyes, misshapen head, small tongue, absent palate, diaphragmatic hernia, edema, and cardiac defects.1 Increased postimplantation loss and decreased numbers of live fetuses also have been observed.1
Glasdegib is not recommended for use during pregnancy.1 Pregnancy status should be verified in women of childbearing potential within 7 days prior to initiation of glasdegib therapy.1 Such patients should use effective contraceptive methods during glasdegib therapy and for at least 30 days after the drug is discontinued.1 The patient should be apprised of the potential risks to the fetus if pregnancy occurs while receiving the drug.1
Male patients should be advised of the potential to expose female sexual partners to glasdegib through semen.1 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 childbearing potential while receiving glasdegib and for at least 30 days after the drug is discontinued.1 In addition, men should not donate semen while receiving glasdegib and for at least 30 days after the drug is discontinued.1
Because of the possibility that the drug may be present in blood and be transfused into a woman who is pregnant, patients receiving glasdegib should not donate blood or blood products during therapy and for at least 30 days after the drug is discontinued.1
Exposure to glasdegib during pregnancy should be reported to the manufacturer by calling 800-438-1985.1
Other Warnings and Precautions
Prolongation of the QTc interval and ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia, may occur in patients receiving glasdegib.1 QTc-interval prolongation appears to occur in a plasma concentration-dependent manner.1 In the principal efficacy study evaluating glasdegib in conjunction with low-dose cytarabine in patients with acute myeloid leukemia (AML), prolongation of the QTc interval by more than 60 msec from baseline occurred in 4% and the QTc interval was prolonged to more than 500 msec in 5% of patients receiving the combined treatment.1
ECGs and serum electrolytes should be monitored periodically during glasdegib therapy.1 Any abnormalities should be managed promptly.1 The manufacturer recommends more frequent ECG monitoring in patients with congenital long QT syndrome, congestive heart failure, or electrolyte abnormalities and in those who are receiving drugs known to prolong the QT interval.1
Withhold glasdegib if QTc increases to >500 msec.1 Discontinue glasdegib permanently for patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.1
Musculoskeletal Adverse Reactions
Musculoskeletal adverse reactions, which may be accompanied by creatine phosphokinase (CPK) elevations, have been reported with glasdegib.1 In the principal efficacy study, musculoskeletal adverse reactions occurred in 45% of patients, with 2% reported as ≥Grade 3.1 The most frequent manifestations were musculoskeletal pain (30%) and muscle spasms (15%).1 Increased CPK laboratory values occurred in 16% of patients.1
Obtain baseline CPK levels prior to initiating glasdegib and as clinically indicated (e.g., if muscle symptoms are reported).1 Obtain CPK and serum creatinine levels at least weekly in patients with musculoskeletal adverse reactions with concurrent CPK elevation >2.5 times the upper limit of normal (ULN) until resolution of clinical signs and symptoms.1 Depending on the severity of symptoms, temporary dose interruption, dose reduction, or discontinuation of glasdegib may be required.1
Glasdegib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1
It is not known whether glasdegib is distributed into human milk or if the drug has any effects on milk production or the nursing infant.1
Because of the potential for serious adverse reactions to glasdegib in nursing infants, women should be advised not to breast-feed or provide breast milk to infants while receiving glasdegib and for at least 30 days after the drug is discontinued.1
Females and Males of Reproductive Potential
Pregnancy status should be verified in women of reproductive potential within 7 days prior to initiation of glasdegib therapy.1 Such patients should use effective contraceptive methods during glasdegib therapy and for at least 30 days after the last dose.1
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.1 In addition, men should not donate semen while receiving glasdegib and for at least 30 days after the last dose.1
Based on findings in animal studies, glasdegib may impair fertility in males of reproductive potential.1 Some effects on male reproductive organs did not recover.1 Men should seek advice on effective fertility preservation before treatment.1
Safety and efficacy of glasdegib have not been established in pediatric patients.1
Animal studies suggest possible adverse effects on bone, teeth, and reproductive tissues in juvenile rats receiving glasdegib for 26 weeks at exposure levels approximately 6.6 times the human exposure at the recommended dosage.1
In the principal efficacy study evaluating glasdegib in conjunction with low-dose cytarabine for AML, 98% of patients were 65 years of age or older and 60% were 75 years of age or older.1 Clinical studies did not include sufficient numbers of patients younger than 65 years of age to determine differences in safety between geriatric and younger adults.1
Mild hepatic impairment (i.e., total bilirubin concentrations between 1-1.5 times the upper limit of normal [ULN] or AST concentrations exceeding the ULN with total bilirubin concentrations not exceeding the ULN) does not have a clinically important effect on the pharmacokinetics of glasdegib.1
In a single-dose pharmacokinetic study, systemic exposure of glasdegib was increased by 11% in individuals with moderate hepatic impairment (Child-Pugh class B) and decreased by 24% in individuals with severe hepatic impairment (Child-Pugh class C) compared with individuals with normal hepatic function.1
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
Mild renal impairment (creatinine clearance of 60-89 mL/minute) does not have clinically important effects on the pharmacokinetics of glasdegib.1
In a single-dose pharmacokinetic study, systemic exposure of glasdegib was increased 2.1-fold in individuals with moderate or severe renal impairment (estimated glomerular filtration rate of 30-59 or 15-29 mL/minute per 1.73 m2, respectively) compared with individuals with normal renal function.1, 6
The effect of end-stage renal disease (ESRD) requiring hemodialysis on the pharmacokinetics of glasdegib has not been studied.1
No dosage adjustment is necessary in patients with renal impairment; however, the manufacturer states that patients with severe renal impairment should be monitored for adverse reactions.1
Adverse effects reported in ≥20% of patients: Anemia, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash.1
Glasdegib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4, with minor contributions by CYP2C8 and uridine diphosphate-glucuronosyltransferase (UGT) 1A9.1 In vitro studies indicate that glasdegib does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A, and does not induce CYP isoenzymes 1A2, 2B6, or 3A.1
Glasdegib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in vitro.1
In vitro studies indicate that glasdegib inhibits P-gp, BCRP, multidrug and toxin extrusion transporters (MATE) 1, and MATE2K, but not 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
Concomitant use of glasdegib and potent CYP3A inhibitors may result in increased glasdegib plasma concentrations and increased risk of adverse effects.1 When the potent CYP3A4 inhibitor ketoconazole (400 mg daily for 7 days) was administered concomitantly with glasdegib (single 200-mg dose) in healthy individuals, peak plasma concentrations and area under the plasma concentration-time curve (AUC) of glasdegib were increased by 1.4- and 2.4-fold, respectively.1, 3
Selection of alternative drugs that are not potent CYP3A inhibitors should be considered.1 If concomitant use of a potent CYP3A inhibitor cannot be avoided, patients should be monitored for adverse effects of glasdegib.1
Concomitant use of glasdegib and moderate or potent CYP3A inducers may result in decreased glasdegib plasma concentrations and reduced efficacy of glasdegib.1 When the potent CYP3A4 inducer rifampin (600 mg daily for 11 days) was administered concomitantly with glasdegib (single 100-mg dose) in healthy individuals, peak plasma concentrations and AUC of glasdegib were decreased by 35 and 70%, respectively.1, 3 Based on pharmacokinetic modeling, concomitant use of glasdegib and the moderate CYP3A4 inducer efavirenz is expected to decrease glasdegib peak plasma concentrations and AUC by 25 and 55%, respectively.1
The manufacturer states that concomitant use of glasdegib and moderate or potent CYP3A4 inducers should be avoided.1 If concomitant use of a moderate CYP3A4 inducer cannot be avoided, the dosage of glasdegib should be increased.1 In patients receiving glasdegib 100 mg once daily, the dosage should be increased to 200 mg once daily, and in those receiving glasdegib 50 mg once daily, the dosage should be increased to 100 mg once daily.1 The previous dosage of glasdegib should be resumed 7 days after the moderate CYP3A4 inducer is discontinued.1
Drugs that Prolong QT Interval
Concomitant use of glasdegib and drugs that prolong the QT interval may increase the risk of QT-interval prolongation and should be avoided.1 Selection of alternative drugs that do not prolong the QT interval should be considered.1 If concomitant use cannot be avoided, patients should be monitored for QT-interval prolongation.1
Drugs Affecting Gastric Acidity
Concomitant administration of rabeprazole (40 mg daily for 7 days) and glasdegib (single 100-mg dose) in healthy individuals decreased peak plasma concentrations of glasdegib by 20%, but did not affect glasdegib AUC.1, 7
Glasdegib is an antineoplastic agent that inhibits the hedgehog pathway by selectively binding to and inhibiting smoothened, a transmembrane protein involved in hedgehog signal transduction.1, 2, 8 The hedgehog signaling pathway plays an important role during embryonic organ and tissue development and is a key regulator in the maintenance and regeneration of tissue, including stem cells, in adults.4, 5, 8 Genetic mutations that allow for aberrant activation of the hedgehog pathway have been implicated in the development of several malignancies, including hematologic malignancies.4, 5, 8 In the hedgehog pathway, activation of smoothened results in activation of glioma (GLI) zinc finger transcription factors, which regulate gene transcription.4, 5, 8 By inhibiting smoothened, glasdegib inhibits expression of activating transcription factor GLI1.3
In xenograft models of human acute myeloid leukemia (AML) in mice, glasdegib in conjunction with low-dose cytarabine inhibited tumor growth and reduced the percentage of CD45+/CD33+ blasts in the marrow to a greater extent than either glasdegib or low-dose cytarabine alone.1
Following oral administration, median time to peak plasma glasdegib concentrations ranges from 1.3-1.8 hours with steady-state concentrations achieved within 8 days.1 The median accumulation ratio ranges from 1.2-2.5.1 Area under the serum concentration-time curve (AUC) and peak plasma concentrations of glasdegib are dose proportional over a dosage range of 5-600 mg once daily.1 The mean absolute bioavailability of glasdegib is 77%.1 Administration with a high-fat, high-calorie meal reduces peak plasma concentrations and AUC by 31 and 16%, respectively; these changes are not considered clinically important.1, 3, 7 Glasdegib is 91% bound to human plasma proteins in vitro.1 Glasdegib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 (60-80%), with minor contributions by CYP2C8 (2-20%) and uridine diphosphate-glucuronosyltransferase (UGT) 1A9.1, 3 Unchanged glasdegib is the major drug component circulating in plasma; no active metabolites have been identified.3 Following a single oral dose of glasdegib in healthy individuals, 49% of the dose is eliminated in urine (17% as unchanged drug) and 42% is excreted in feces (20% as unchanged drug).1, 3 The mean half-life of glasdegib is 17.4 hours following once daily dosing in patients with hematologic malignancies.1
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].
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.
Glasdegib can only be obtained through designated specialty pharmacies and distributors.10 Contact manufacturer for additional information.10
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 25 mg (of glasdegib) | Pfizer | |
100 mg (of glasdegib) | Daurismo® | Pfizer |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions June 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Pfizer Inc. Daurismo® (glasdegib maleate) tablets prescribing information. New York, NY; 2023 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. [PubMed 30555165]
3. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 210656Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]
4. Gupta S, Takebe N, Lorusso P. Targeting the Hedgehog pathway in cancer. Ther Adv Med Oncol . 2010; 2:237-50. [PubMed 21789137]
5. Irvine DA, Copland M. Targeting hedgehog in hematologic malignancy. Blood . 2012; 119:2196-204. [PubMed 22223823]
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. [PubMed 30536154]
8. Terao T, Minami Y. Targeting Hedgehog (Hh) Pathway for the Acute Myeloid Leukemia Treatment. Cells . 2019; 8 [PubMed 30987263]
9. Food and Drug Administration. FDA Application: Search orphan drug designations and approvals. Silver Spring, MD. From FDA website. [Web]
10. Pfizer, Inc. Pfizer Oncology Together website. Accessed 2024 Apr 26. [Web]
100. Sekeres M, Guyatt G, Abel G, et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood Adv. 2020;4(15):3528-49.