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.
Note: Verify pregnancy status of females of reproductive potential within 7 days prior to therapy initiation.
Acute myeloid leukemia: 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.
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.
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 the in manufacturer’s labeling (has not been studied).
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.
Refer to adult dosing.
Hematologic toxicity:
Neutrophils <500/mm3 for more than 42 days (in the absence of disease): Discontinue glasdegib (and low-dose cytarabine) permanently.
Platelets <10,000/mm3 for more than 42 days (in the absence of disease): Discontinue glasdegib (and low-dose cytarabine) permanently.
Nonhematologic toxicity:
QTc prolongation (on at least 2 separate electrocardiograms [ECGs]:
QTc interval >480 to 500 msec: Assess electrolytes and supplement as necessary; 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 necessary; 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: Discontinue glasdegib permanently.
Other toxicity:
Grade 3: 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: Discontinue glasdegib (and low-dose cytarabine) permanently.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as maleate:
Daurismo: 25 mg, 100 mg
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as maleate:
Daurismo: 25 mg, 100 mg
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
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/2020/210656s002s004lbl.pdf#page=20
Oral: Administer with or without food at approximately the same time each day. Do not split or crush the tablets.
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.
Acute myeloid leukemia: 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.
Glasdegib may be confused with gefitinib, gilteritinib, sonidegib, vismodegib
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.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Edema (30%), atrial arrhythmia (13%), chest pain (12%)
Central nervous system: Fatigue (36%), dizziness (18%), headache (12%)
Dermatologic: Skin rash (20%)
Endocrine & metabolic: Hyponatremia (11% to 54%), hypomagnesemia (33%), hyperkalemia (16%), hypokalemia (15%), weight loss (13%)
Gastrointestinal: Nausea (29%), decreased appetite (21%), dysgeusia (21%), mucositis (21%; grade ≥3: 1%), constipation (20%), abdominal pain (19%), diarrhea (18%), vomiting (18%)
Hematologic & oncologic: Anemia (43%; grade ≥3: 41%), hemorrhage (36%; grade ≥3: 6%), febrile neutropenia (31%; grade ≥3: 31%), thrombocytopenia (30%; grade ≥3: 30%), decreased white blood cell count (11%; grade ≥3: 11%)
Hepatic: Increased serum aspartate aminotransferase (28%), increased serum bilirubin (25%), increased serum alanine aminotransferase (24%), increased serum alkaline phosphatase (23%)
Neuromuscular & skeletal: Musculoskeletal pain (30%), increased creatine phosphokinase in blood specimen (16%), muscle spasm (15%)
Renal: Increased serum creatinine (96%), renal insufficiency (19%)
Respiratory: Dyspnea (23%), pneumonia (19%), cough (18%)
Miscellaneous: Fever (18%)
1% to 10%:
Cardiovascular: Prolonged QT interval on ECG (4% to 5%)
Infection: Sepsis (7%)
Frequency not defined: Endocrine & metabolic: Hypophosphatemia
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.
Concerns related to adverse effects:
• 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.
Disease-related concerns:
• Renal impairment: Patients with severe impairment are at increased risk of adverse reactions (including QTc interval prolongation) due to increased glasdegib concentrations; monitor closely.
Special populations:
• Pregnancy: [US Boxed Warning]: Glasdegib can cause embryo-fetal death or severe birth defects when administered to a pregnant female. 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 glasdegib treatment and for at least 30 days after the last glasdegib 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 glasdegib treatment and for at least 30 days after the last glasdegib dose to avoid potential drug exposure.
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.
Substrate of BCRP/ABCG2, CYP2C8 (minor), CYP3A4 (major), UGT1A9; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
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
[US Boxed Warning]: Conduct pregnancy testing in females of reproductive potential prior to initiation of glasdegib treatment. Pregnancy testing should be conducted within 7 days prior to starting glasdegib treatment. Advise females of reproductive potential to use effective contraception during treatment and for at least 30 days after the last glasdegib dose.
[US Boxed Warning]: 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 glasdegib treatment and for at least 30 days after the last glasdegib dose to avoid potential drug exposure. Effective contraception, including a condom, should be used by males 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.
Glasdegib use is not recommended in pregnant females. [US Boxed Warning]: Glasdegib can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. Glasdegib is embryotoxic, fetotoxic, and teratogenic in animals. Glasdegib inhibits the Hedgehog pathway, which is critical to fetal development (Walterhouse 1999).
Data collection to monitor pregnancy and infant outcomes following exposure to glasdegib is ongoing. Health care providers are encouraged to enroll females inadvertently exposed to glasdegib during pregnancy to the Pfizer pregnancy registry (800-438-1985).
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.
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 serum creatine kinase levels prior to therapy initiation and as clinically indicated; pregnancy test (within 7 days prior to starting glasdegib treatment in females of reproductive potential); 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 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.
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.
Distribution: 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)
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.
Tablets (Daurismo Oral)
25 mg (per each): $393.72
100 mg (per each): $787.44
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