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Glasdegib Maleate

Class: Antineoplastic Agents
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 Dec 17, 2018.

Warning

Warning: Embryo-fetal Toxicity1

See full prescribing information for complete boxed warning.1

  • Glasdegib maleate can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. Glasdegib maleate is embryotoxic, fetotoxic, and teratogenic in animals.1

  • Conduct pregnancy testing in females of reproductive potential prior to initiation of glasdegib maleate treatment. Advise females of reproductive potential to use effective contraception during treatment with glasdegib maleate and for at least 30 days after the last dose.1

  • Advise males of the potential risk of exposure through semen and to use condoms with a pregnant partner or a female partner of reproductive potential during treatment with glasdegib maleate and for at least 30 days after the last dose to avoid potential drug exposure.1

Introduction

See also: Xospata

Glasdegib maleate is an antineoplastic agent.

Uses for Glasdegib Maleate

Glasdegib maleate has the following uses:

Glasdegib maleate 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.1

Glasdegib maleate has the following limitation of use:

Glasdegib maleate has not been studied in patients with the comorbidities of severe renal impairment or moderate-to-severe hepatic impairment.1

Glasdegib Maleate Dosage and Administration

General

Glasdegib maleate is available in the following dosage form(s) and strength(s):

Tablets: 100 mg, 25 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

Recommended dose: 100 mg (of glasdegib) 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.1 For patients without unacceptable toxicity, treat for a minimum of 6 cycles to allow time for clinical response.1

Cautions for Glasdegib Maleate

Contraindications

None.1

Warnings/Precautions

Embryo-fetal Toxicity

Based on its mechanism of action and findings from animal embryo-fetal developmental toxicity studies, glasdegib maleate can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. There are no clinical data on the use of glasdegib maleate in pregnant women. In animal embryo-fetal developmental toxicity studies, glasdegib caused embryotoxicity, fetotoxicity, and teratogenicity at maternal exposures that were less than the human exposure at the recommended human dose of 100 mg. Advise pregnant women of the potential risk to the fetus.1

Females of Reproductive Potential

Glasdegib maleate is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating glasdegib maleate treatment. Advise females of reproductive potential to use effective contraception during treatment with glasdegib maleate and for at least 30 days after the last dose. Advise women not to breastfeed during treatment with glasdegib maleate and for at least 30 days after the last dose.1

Males

Advise male patients with female partners of the potential risk of exposure through semen and to use effective contraception, including a condom, even after vasectomy, to avoid drug exposure to a pregnant partner or a female partner of reproductive potential during treatment with glasdegib maleate and for at least 30 days after the last dose.1

Blood Donation

Advise patients not to donate blood or blood products while taking glasdegib maleate and for at least 30 days after the last dose of glasdegib maleate because their blood or blood products might be given to a female of reproductive potential.1

QTc Interval Prolongation

Patients treated with glasdegib maleate can develop QTc prolongation and ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia. Of the 98 evaluable patients treated with glasdegib maleate 100 mg in combination with low-dose cytarabine in the clinical trial, 5% were found to have a QTc interval greater than 500 ms and 4% of patients had an increase from baseline QTc greater than 60 ms. The clinical trial excluded patients with baseline QTc of greater than 470 ms or with a history of long QT syndrome or uncontrolled cardiovascular disease.1

Monitor electrocardiograms (ECGs) and electrolytes. Concomitant use of glasdegib maleate with drugs known to prolong the QTc interval and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. In patients with congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, more frequent ECG monitoring is recommended.1

Interrupt glasdegib maleate if QTc increases to greater than 500 ms. Discontinue glasdegib maleate permanently for patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.1

Specific Populations

Pregnancy

Risk Summary: Based on its mechanism of action and findings in animal embryo-fetal developmental toxicity studies, glasdegib maleate can cause fetal harm when administered to a pregnant woman. There are no clinical data on the use of glasdegib maleate in pregnant women to inform of a drug-associated risk of major birth defects and miscarriage. Glasdegib maleate is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating treatment with glasdegib maleate. Report pregnancy exposures to Pfizer at 1-800-438-1985. In animal embryo-fetal developmental toxicity studies, repeat-dose oral administration of glasdegib maleate during organogenesis at maternal exposures that were less than the human exposure at the recommended dose resulted in embryotoxicity, fetotoxicity and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

Animal Data: In embryo-fetal developmental toxicity studies, glasdegib was orally administered to pregnant rats and rabbits at doses up to 100 mg/kg/day during the period of organogenesis. Glasdegib resulted in embryo-fetal lethality (e.g., increased postimplantation loss and decreased numbers of live fetuses) in rats and rabbits at 50 mg/kg/day and 5 mg/kg/day, respectively, at maternal exposures approximately 4 times and 3 times the human exposure at the recommended dose [based on Cmax (rat) and AUC (rabbit)]. Doses of ≥ 10 mg/kg in rat [approximately 0.6 times the human exposure (Cmax) at the recommended dose] and ≥ 5 mg/kg in rabbit resulted in 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.1

Lactation

Risk Summary: There are no data on the presence of glasdegib or its active metabolites in human milk, the effects of the drug on the breastfed child, or its effect on milk production. Because of the potential for serious adverse reactions in a breastfed child from glasdegib maleate, advise women who are taking glasdegib maleate not to breastfeed or provide breast milk to infants or children during treatment with glasdegib maleate and for at least 30 days after the last dose.1

Females and Males of Reproductive Potential

Glasdegib maleate can cause fetal harm when administered to a pregnant woman.1

Conduct pregnancy testing in females of reproductive potential within 7 days prior to initiating therapy with glasdegib maleate.1

Advise females of reproductive potential to use effective contraception during treatment with glasdegib maleate and at least 30 days after the last dose.1

It is not known if glasdegib is 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 with glasdegib maleate and for at least 30 days after the last dose. Advise males to not donate semen during treatment with glasdegib maleate and for at least 30 days after the last dose.1

Based on findings in repeat-dose animal toxicity studies in rats, glasdegib maleate 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.1

Pediatric Use

The safety and effectiveness of glasdegib maleate have not been established in pediatric patients. In repeat-dose toxicity studies in rats, oral administration of glasdegib maleate resulted in adverse changes in growing bone, teeth, and testis. Effects on bone consisted of partial to complete closure of the epiphyseal plate. Effects in growing incisor teeth included degeneration/necrosis of ameloblasts, and complete tooth loss with oral ulceration. Reproductive tissue toxicity was evidenced by testicular degeneration and hypospermatogenesis. These effects in bone, teeth and testis were observed after administration of glasdegib maleate for 26 weeks at greater than or equal to 50 mg/kg/day corresponding to approximately 6.6 times the steady state AUC in patients at the recommended human dose.1

Geriatric Use

Of the total number of subjects in clinical studies of glasdegib maleate with low-dose cytarabine (N=88), 98% of the patients were age 65 years or older and 60% of the patients were age 75 years or older. There were insufficient patients younger than age 65 years to determine differences in adverse reactions reported from patients older than 65.1

Common Adverse Effects

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.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Strong CYP3A4 Inhibitors: Consider alternative therapies that are not strong CYP3A inhibitors or monitor for increased risk of adverse reactions, including QTc interval prolongation.1

  • Strong CYP3A4 Inducers: Avoid concomitant use with glasdegib maleate.1

  • QTc Prolonging Drugs: Avoid co-administration with glasdegib maleate. If co-administration is unavoidable, monitor for increased risk of QTc interval prolongation.1

Actions

Mechanism of Action

Glasdegib is an inhibitor of the Hedgehog pathway. Glasdegib binds to and inhibits Smoothened, a transmembrane protein involved in hedgehog signal transduction.1

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.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).1

Embryo-Fetal Toxicity

Advise female patients of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. Advise female patients and female partners of male patients to contact their healthcare provider with a known or suspected pregnancy. 1

Females and Males of Reproductive Potential

Advise females of reproductive potential to use effective contraception during treatment with glasdegib maleate and for at least 30 days after the last dose. 1

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 with glasdegib maleate and for at least 30 days after the last dose. 1

Semen Donation

Advise males not to donate semen during treatment with glasdegib maleate and for at least 30 days after the last dose of glasdegib maleate.1

Lactation

Advise women not to breastfeed during treatment with glasdegib maleate and for at least 30 days after the last dose of glasdegib maleate.1

Blood Donation

Advise patients not to donate blood or blood products during treatment with glasdegib maleate and for at least 30 days after the last dose of glasdegib maleate.1

Infertility

Advise males of reproductive potential of the potential for impaired fertility from glasdegib maleate. Advise male patients to seek advice on effective fertility preservation before treatment.1

QT Interval Prolongation

Inform patients of signs and symptoms that may be indicative of significant QT interval prolongation. Advise patients to contact their healthcare provider immediately in the event of syncope, pre-syncopal symptoms, and cardiac palpitations.1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

Glasdegib Maleate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, Film Coated

25 mg (of glasdegib)

Daurismo

Pfizer Laboratories Div Pfizer Inc

100 mg (of glasdegib)

Daurismo

Pfizer Laboratories Div Pfizer Inc

AHFS Drug Information. © Copyright 2019, Selected Revisions December 17, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Pfizer Laboratories Div Pfizer Inc. Daurismo (glasdegib) ORAL prescribing information. 2018 Nov. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=204a6f7e-c9a4-472b-abd2-9527bda64d17

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