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Glasdegib: Drug information

Glasdegib: Drug information
(For additional information see "Glasdegib: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Embryo-fetal toxicity:

Glasdegib can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. Glasdegib is embryotoxic, fetotoxic, and teratogenic in animals. Conduct pregnancy testing in females of reproductive potential prior to initiation of glasdegib treatment. Advise females of reproductive potential to use effective contraception during treatment with glasdegib and for at least 30 days after the last dose. Advise males of the potential risk of glasdegib exposure through semen and to use condoms with a pregnant partner or a female partner of reproductive potential during treatment with glasdegib and for at least 30 days after the last dose to avoid potential drug exposure.

Brand Names: US
  • Daurismo
Brand Names: Canada
  • Daurismo
Pharmacologic Category
  • Antineoplastic Agent, Hedgehog Pathway Inhibitor
Dosing: Adult

Note: Verify pregnancy status within 7 days prior to therapy initiation (in patients who could become pregnant).

Acute myeloid leukemia, newly diagnosed

Acute myeloid leukemia, newly diagnosed : Adults ≥75 years or with comorbidities: Oral: 100 mg once daily (in combination with subcutaneous low-dose cytarabine) for a minimum of 6 (28-day) cycles (to allow time for clinical response) or until disease progression or unacceptable toxicity (Ref).

Missed or vomited doses: If a dose is missed, 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. Do not administer 2 doses within 12 hours. If a dose is vomited, do not administer a replacement dose. Resume dosing with the next scheduled dose.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

eGFR >29 mL/minute: No dosage adjustment necessary.

eGFR 15 to 29 mL/minute: No dosage adjustment necessary; however, due to increased glasdegib concentrations, patients with severe impairment are at increased risk of adverse reactions (including QTc interval prolongation); monitor closely.

eGFR <15 mL/minute (including end-stage renal disease requiring dialysis): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment: Adult

Mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to 1.5 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling; however, mild hepatic impairment had no clinically meaningful effect on glasdegib pharmacokinetics.

Moderate (total bilirubin 1.5 to 3 times ULN and any AST) or severe (total bilirubin >3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Adjustment for Toxicity: Adult
Glasdegib Recommended Dosage Modifications for Adverse Reactions

Adverse reaction

Severity

Glasdegib dosage modification

Hematologic toxicity

Platelets <10,000/mm3 for >42 days (in the absence of disease)

Permanently discontinue glasdegib (and low-dose cytarabine).

Neutrophils <500/mm3 for >42 days (in the absence of disease)

Permanently discontinue glasdegib (and low-dose cytarabine).

Musculoskeletal adverse reactions

Grade 3 (severe) or serum CPK elevation between 2.5 to 10 times the ULN

Interrupt glasdegib therapy until symptoms reduce to mild or return to baseline.

Obtain CPK and serum creatinine levels at least weekly until resolution of clinical signs/symptoms.

Resume glasdegib at the same dose level, or at a reduced dose of 50 mg.

If toxicity recurs, discontinue glasdegib.

Grade 4 (life-threatening) or serum CPK elevation >10 times the ULN

Discontinue glasdegib.

QTc interval prolongation (on at least 2 separate ECGs)

QTc interval >480 to 500 msec

Assess electrolytes and supplement as clinically indicated.

Review and adjust concomitant medications with known QTc interval-prolonging effects.

Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation to ≤480 msec.

QTc interval >500 msec

Interrupt glasdegib therapy.

Assess electrolytes and supplement as clinically indicated.

Review and adjust concomitant medications with known QTc interval-prolonging effects.

When QTc interval returns to within 30 msec of baseline or ≤480 msec, resume glasdegib at a reduced dose of 50 mg once daily.

Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation.

Consider increasing the glasdegib dose back to 100 mg once daily if an alternate etiology for the QTc prolongation is identified.

QTc interval prolongation with life-threatening arrhythmia

Permanently discontinue glasdegib.

Other adverse reactions

Grade 3 (severe)

Interrupt glasdegib and/or low-dose cytarabine until symptoms reduce to mild or return to baseline.

Resume glasdegib at the same dose or at a reduced dose of 50 mg (also resume low-dose cytarabine at the same or a reduced dose).

If toxicity recurs, discontinue glasdegib (and low-dose cytarabine unless toxicity is attributable to glasdegib only).

Grade 4 (life-threatening)

Permanently discontinue glasdegib (and low-dose cytarabine).

Dosing: Older Adult

Refer to adult dosing.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported with combination therapy in adults.

>10%:

Cardiovascular: Atrial arrhythmia (13%), chest pain (12%), edema (30%)

Dermatologic: Skin rash (20%)

Endocrine & metabolic: Hyperkalemia (16%), hypokalemia (15%), hypomagnesemia (33%), hyponatremia (11% to 54%), weight loss (13%)

Gastrointestinal: Abdominal pain (19%), constipation (20%), decreased appetite (21%), diarrhea (18%; grades ≥3: 4%), dysgeusia (21%), nausea (29%; grades ≥3: 1%), stomatitis (21%; grades ≥3: 1%), vomiting (18%; grades ≥3: 2%)

Hematologic & oncologic: Anemia (43%; grades ≥3: 41%), decreased white blood cell count (11%; grades ≥3: 11%), febrile neutropenia (31%; grades ≥3: 31%), hemorrhage (36%; grades ≥3: 6%), thrombocytopenia (30%; grades ≥3: 30%)

Hepatic: Increased serum alanine aminotransferase (24%), increased serum alkaline phosphatase (23%), increased serum aspartate aminotransferase (28%), increased serum bilirubin (25%)

Nervous system: Dizziness (18%), fatigue (36%; including asthenia), headache (12%)

Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (16%), musculoskeletal signs and symptoms (45%; including muscle spasm [15%], musculoskeletal pain [30%])

Renal: Increased serum creatinine (96%), renal insufficiency (19%)

Respiratory: Cough (18%), dyspnea (23%), pneumonia (19%)

Miscellaneous: Fever (18%)

1% to 10%:

Cardiovascular: Prolonged QT interval on ECG (4% to 5%)

Dermatologic: Alopecia (<10%)

Infection: Sepsis (7%)

Frequency not defined: Endocrine & metabolic: Hypophosphatemia

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to glasdegib or any component of the formulation; pregnancy; breastfeeding; males or females of childbearing potential who do not comply with effective contraceptive measures; children and adolescents <18 years of age.

Warnings/Precautions

Concerns related to adverse effects:

• Musculoskeletal effects: Musculoskeletal adverse reactions, which may be accompanied by CPK elevations, have occurred with glasdegib (and with other medications that inhibit the hedgehog pathway). Musculoskeletal adverse reactions occurred in almost half of patients; grade 3 or higher were reported in a small percentage of patients. The most frequent manifestations were musculoskeletal pain and muscle spasms. Increased CPK was also reported.

• QTc prolongation: QTc prolongation and ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia may occur. A small percentage of patients in a clinical trial were found to have a QTc interval >500 msec; some patients had an increase from baseline >60 msec. Patients with baseline QTc >470 msec (or with a history of long QT syndrome or uncontrolled cardiovascular disease) were excluded from the clinical trial. Concomitant use of drugs known to prolong the QTc interval and CYP3A4 inhibitors may increase the risk of QTc interval prolongation. Monitor electrocardiograms (ECGs) and electrolytes; patients with congenital long QT syndrome, heart failure, electrolyte abnormalities, or those on concomitant medications known to prolong the QTc interval may require more frequent ECG monitoring. QTc interval prolongation may require therapy interruption, dose reduction, and/or permanent discontinuation.

Other warnings/precautions:

• Blood donation: Advise patients not to donate blood or blood products during glasdegib treatment and for at least 30 days after the last glasdegib dose.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as maleate:

Daurismo: 25 mg, 100 mg

Generic Equivalent Available: US

No

Pricing: US

Tablets (Daurismo Oral)

25 mg (per each): $429.87

100 mg (per each): $859.73

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as maleate:

Daurismo: 25 mg, 100 mg

Prescribing and Access Restrictions

In Canada, glasdegib is available only through the DAURISMO Pregnancy Prevention Program (DPPP). For further information on product availability and prescribing instructions call 1-844-616-6888

Administration: Adult

Oral: Administer with or without food at approximately the same time each day. Do not chew, split, or crush the tablets.

Hazardous Drugs Handling Considerations

This medication is not on the NIOSH (2016) list; however, it meets the criteria for a hazardous drug. Glasdegib may cause teratogenicity, reproductive toxicity, and has a structural or toxicity profile similar to existing hazardous agents.

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Daurismo: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/210656s005lbl.pdf#page=20

Use: Labeled Indications

Acute myeloid leukemia, newly diagnosed: Treatment of newly diagnosed acute myeloid leukemia (in combination with low-dose cytarabine) in adult patients who are ≥75 years of age or who have comorbidities that preclude use of intensive induction chemotherapy.

Medication Safety Issues
Sound-alike/look-alike issues:

Glasdegib may be confused with gefitinib, gilteritinib, sonidegib, vismodegib

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

Metabolism/Transport Effects

Substrate of BCRP/ABCG2, CYP2C8 (minor), CYP3A4 (major), UGT1A9; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Glasdegib. Management: Avoid use of glasdegib and moderate CYP3A4 inducers whenever possible. If combined, increase glasdegib dose from 100 mg daily to 200 mg daily or from 50 mg daily to 100 mg daily. Resume previous glasdegib dose 7 days after discontinuation of the inducer. Risk D: Consider therapy modification

CYP3A4 Inducers (Strong): May decrease the serum concentration of Glasdegib. Risk X: Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Glasdegib. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Glasdegib. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor closely for evidence of QT interval prolongation and other adverse reactions to glasdegib. Risk D: Consider therapy modification

Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Reproductive Considerations

Evaluate pregnancy status prior to use; verify the patient is not pregnant within 7 days prior to treatment initiation in patients who could become pregnant. Patients who could become pregnant should use effective contraception during therapy and for at least 30 days after the last dose of glasdegib.

Patients with partners who are or who could become pregnant should also use effective contraception during therapy and for at least 30 days after the last glasdegib dose. Effective contraception, which includes use of a condom to prevent potential exposure via semen, should be used even after vasectomy. Semen should not be donated during treatment and for at least 30 days after the last dose of glasdegib. Based on animal data, males should consider effective fertility preservation prior to therapy.

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to glasdegib may cause fetal harm. Glasdegib inhibits the hedgehog pathway, which is critical to fetal development (Villavicencio 2000; Walterhouse 1999). Embryo-fetal death or severe birth defects may occur following exposure to glasdegib.

The European Society for Medical Oncology has published guidelines for the diagnosis, treatment, and follow-up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team) approach (ESMO [Peccatori 2013]). Glasdegib is not recommended for use in pregnant patients.

Data collection to monitor pregnancy and infant outcomes following exposure to glasdegib is ongoing. Health care providers are encouraged to enroll persons inadvertently exposed to glasdegib during pregnancy to the Pfizer pregnancy registry (800-438-1985).

Breastfeeding Considerations

It is not known if glasdegib is present in breast milk.

Due to the potential for adverse events in a breastfed infant, the manufacturer does not recommend breastfeeding during therapy and for at least 30 days after the last glasdegib dose.

Monitoring Parameters

Monitor complete blood counts, electrolytes, renal, and hepatic function prior to therapy and at least once weekly for the first month; monitor electrolytes and renal function once monthly for the duration of therapy (or as clinically indicated). Obtain CPK levels prior to therapy initiation and as clinically indicated (eg, if muscle symptoms are reported); obtain CPK and serum creatinine at least weekly in patients with musculoskeletal adverse reactions with concurrent CPK elevation >2.5 times ULN and continue until resolution of clinical signs and symptoms. Conduct pregnancy testing within 7 days prior to starting glasdegib treatment (in patients who could become pregnant). Monitor ECGs prior to therapy initiation, ~1 week after initiation, and then once monthly for the next 2 months; more frequent monitoring may be necessary (repeat ECG if abnormal). Monitor for signs/symptoms of musculoskeletal adverse reactions. Monitor adherence.

The American Society of Clinical Oncology hepatitis B virus screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.

Mechanism of Action

Glasdegib is a small molecule inhibitor of the Hedgehog pathway. Glasdegib binds to and inhibits Smoothened (SMO), which is a transmembrane protein involved in hedgehog signal transduction. Glasdegib blocks the translocation of SMO into cilia and prevents SMO-mediated activation of downstream Hedgehog targets (Cortes 2018). In an animal AML model, glasdegib (in combination with low-dose cytarabine) reduced the percentage of CD45+/CD33+ blasts in the bone marrow and inhibited increases in tumor size to a greater extent than either agent alone.

Pharmacokinetics (Adult Data Unless Noted)

Distribution: Vz/F: 188 L.

Protein binding: 91% to human plasma proteins.

Metabolism: Primarily hepatic via CYP3A4, with minor contributions by CYP2C8 and UGT1A9.

Bioavailability: 77%.

Half-life elimination: 17.4 hours ± 3.7 hours.

Time to peak: 1.3 to 1.8 hours.

Excretion: Urine: 49% (17% as unchanged drug); Feces: 42% (20% as unchanged drug).

Clearance: 6.45 L/hour.

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Altered kidney function: Following administration of a single 100 mg dose, glasdegib AUC0-inf increased by 2.1-fold in subjects with eGFR 15 to 59 mL/minute compared to subjects with normal renal function (eGFR ≥90 mL/minute).

Hepatic function impairment: Following administration of a single 100 mg dose, glasdegib AUC0-inf increased by 11% in subjects with moderate impairment (Child-Pugh class B) and decreased by 24% in subjects with severe impairment (Child-Pugh class C), compared to subjects with normal hepatic function.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AT) Austria: Daurismo;
  • (CZ) Czech Republic: Daurismo;
  • (DE) Germany: Daurismo;
  • (FI) Finland: Daurismo;
  • (GB) United Kingdom: Daurismo;
  • (GR) Greece: Daurismo;
  • (IT) Italy: Daurismo;
  • (NO) Norway: Daurismo;
  • (PR) Puerto Rico: Daurismo;
  • (PT) Portugal: Daurismo;
  • (RO) Romania: Daurismo;
  • (SI) Slovenia: Daurismo
  1. <800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 43-NF 38). Rockville, MD: United States Pharmacopeia Convention; 2020:74-92.
  2. Cortes JE, Douglas Smith B, Wang ES, et al. Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results. Am J Hematol. 2018;93(11):1301-1310. [PubMed 30074259]
  3. Cortes JE, Heidel FH, Fiedler W, et al. Survival outcomes and clinical benefit in patients with acute myeloid leukemia treated with glasdegib and low-dose cytarabine according to response to therapy. J Hematol Oncol. 2020;13(1):92. doi:10.1186/s13045-020-00929-8 [PubMed 32664995]
  4. 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(2):379-389. doi:10.1038/s41375-018-0312-9 [PubMed 30555165]
  5. Daurismo (glasdegib) [prescribing information]. New York, NY: Pfizer Labs; March 2023.
  6. Daurismo (glasdegib) [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada ULC; October 2022.
  7. Heuser M, Smith BD, Fiedler W, et al. Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial. Ann Hematol. 2021;100(5):1181-1194. doi:10.1007/s00277-021-04465-4 [PubMed 33740113]
  8. Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol. 2020;38(31):3698-3715. doi:10.1200/JCO.20.01757 [PubMed 32716741]
  9. Peccatori FA, Azim HA Jr, Orecchia R, et al; ESMO Guidelines Working Group. Cancer, pregnancy and fertility: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):S160-S170. doi:10.1093/annonc/mdt199 [PubMed 23813932]
  10. Refer to manufacturer's labeling.
  11. US Department of Health and Human Services; Centers for Disease Control and Prevention; National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings 2016. https://www.cdc.gov/niosh/docs/2016-161/default.html. Updated September 2016. Accessed November 28, 2020.
  12. Villavicencio EH, Walterhouse DO, Iannaccone PM. The sonic hedgehog-patched-gli pathway in human development and disease. Am J Hum Genet. 2000;67(5):1047-1054. doi:10.1016/S0002-9297(07)62934-6 [PubMed 11001584]
  13. Walterhouse DO, Yoon JW, Iannaccone PM. Developmental pathways: Sonic hedgehog-Patched-GLI. Environ Health Perspect. 1999;107(3):167-171. [PubMed 10064544]
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