glasdegib (Rx)

Brand and Other Names:Daurismo
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 25mg
  • 100mg

Acute Myeloid Leukemia

Indicated, in combination with low-dose cytarabine, for newly diagnosed acute myeloid leukemia (AML) in adults aged ≥75 years or who have comorbidities that preclude use of intensive induction chemotherapy

100 mg PO qDay on days 1-28 of each 28-day cycle; administer in combination with cytarabine 20 mg SC BID on days 1-10

For patients without unacceptable toxicity, treat for a minimum of 6 cycles to allow time for clinical response

Dosage Modifications

QT prolongation (≥2 separate ECGs)

  • QTc >480 to 500 ms
    • Assess electrolyte levels 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 QTc prolongation resolution to ≤480 ms
  • QT >500 ms
    • Assess electrolyte levels and supplement as clinically indicated
    • Review and adjust concomitant medications with known QTc interval-prolonging effects
    • Interrupt glasdegib dosing; resume at reduced dose of 50 mg qDay when QTc interval returns to within 30 ms of baseline or ≤480 ms
    • Monitor ECGs at least weekly for 2 weeks following QTc prolongation resolution
    • Consider re-escalating glasdegib dose to 100 mg qDay if other etiology identified for QTc prolongation
  • QTc prolongation with life-threatening arrhythmia
    • Discontinue permanently

Hematologic toxicity

  • Platelets <10 Gi/L or neutrophil count <0.5 Gi/L for >42 days in absence of disease: Discontinue glasdegib and cytarabine permanently

Nonhematologic toxicity

  • Grade 3
    • Interrupt glasdegib and/or cytarabine until symptoms reduce to mild or return to baseline
    • Resume glasdegib at the same dose level, or reduce dose to 50 mg
    • Resume cytarabine at the same dose level, or reduce dose to 15 mg or 10 mg
    • If toxicity recurs, discontinue glasdegib and cytarabine
    • If toxicity attributed only to glasdegib, cytarabine may be continued
  • Grade 4
    • Discontinue glasdegib and cytarabine permanently

Renal or hepatic impairment

  • Not studied

Dosing Considerations

Limitations of use: Not studied in patients with severe renal impairment or moderate-to-severe hepatic impairment

Conduct pregnancy testing in females of reproductive potential before initiating

Monitoring

  • Assess complete blood cell counts, electrolytes, renal function, and hepatic function before initiating and at least once weekly for the first month
  • Monitor electrolytes and renal function once monthly for the duration of therapy
  • Obtain serum creatine kinase levels before initiating and as indicated clinically thereafter (eg, if muscle symptoms are reported)
  • Monitor ECG) before initiating, ~1 week after initiation, and then once monthly for the next 2 months to assess for QTc prolongation; repeat ECG if abnormal; certain patients may require more frequent and ongoing ECG monitoring

Geriatric Dosing

See adult dosing

Of the total number of patients in clinical trials, 98% were aged ≥65 years and 60% were aged ≥75 years

There were insufficient patients younger than age 65 years to determine differences in adverse reactions reported from patients older than 65 years

Safety and efficacy not established

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Interactions

Interaction Checker

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            Adverse Effects

            >10% (All Grades Glasdegib with Cytarabine)

            Increased creatinine (96%)

            Hyponatremia (11-54%)

            Anemia (43%)

            Hemorrhage (36%)

            Fatigue (36%)

            Hypomagnesemia (33%)

            Febrile neutropenia (31%)

            Thrombocytopenia (30%)

            Edema (30%)

            Musculoskeletal pain (30%)

            Nausea (29%)

            Increased AST (28%)

            Increased blood bilirubin (25%)

            Increased ALT (24%)

            Increased alkaline phosphatase (23%)

            Mucositis (21%)

            Decreased appetite (21%)

            Dysgeusia (21%)

            Constipation (20%)

            Rash (20%)

            Abdominal pain (19%)

            Pneumonia (19%)

            Renal insufficiency (19%)

            Pyrexia (18%)

            Diarrhea (18%)

            Vomiting (18%)

            Dizziness (18%)

            Hyperkalemia (16%)

            Increased CPK (16%)

            Muscle spasm (15%)

            Decreased platelet count (15%)

            Hypokalemia (15%)

            Weight decreased (13%)

            Atrial arrhythmia (13%)

            Chest pain (12%)

            Headache (12%)

            >10% (Glasdegib with Cytarabine Grade ≥3)

            Anemia (41%)

            Febrile neutropenia (31%)

            Thrombocytopenia (30%)

            Pneumonia (15%)

            Decreased platelet count (15%)

            Fatigue (14%)

            Dyspnea (11%)

            Decreased WBC count (11%)

            1-10% (Glasdegib with Cytarabine Grade ≥3)

            Hyponatremia (7%)

            Hemorrhage (6%)

            Hyponatremia (6%)

            Renal insufficiency (5%)

            Diarrhea (4%)

            Atrial arrhythmia (4%)

            Increased blood bilirubin (4%)

            Musculoskeletal pain (2%)

            Vomiting (2%)

            Rash (2%)

            Mucositis (1%)

            Pyrexia (1%)

            Chest pain (1%)

            Nausea (1%)

            Constipation (1%)

            Decreased appetite (1%)

            Increased creatinine (1%)

            Increased AST (1%)

            Hyperkalemia (1%)

            1-10% (Glasdegib with Cytarabine)

            <10%

            • Dental disorders: Loose teeth, toothache
            • Skin and subcutaneous tissue disorders: Alopecia
            • Cardiac disorders: QT prolongation
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            Warnings

            Black Box Warnings

            Embryo-fetal toxicity

            • Can cause embryo-fetal death or severe birth defects when administered to pregnant women; it is embryotoxic, fetotoxic, and teratogenic in animals
            • Conduct pregnancy testing in females of reproductive potential before initiating
            • Advise females of reproductive potential to use effective contraception during treatment and for at least 30 days after last dose
            • 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 and for at least 30 days after last dose

            Contraindications

            None

            Cautions

            Based on mechanism of action and findings from animal studies, can cause embryo-fetal death or severe birth defects when administered to pregnant women (see Black Box Warnings and Pregnancy)

            Development of QTc prolongation and ventricular arrhythmias reported, including ventricular fibrillation and ventricular tachycardia; more frequent ECG monitoring advised in patients with congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval (see Drug Interactions)

            Drug interaction overview

            • Glasdegib primarily metabolized by CYP3A
            • Strong CYP3A inhibitors
              • Coadministration may increase glasdegib plasma concentrations and increase risk for QT prolongation
            • Strong CYP3A inducers
              • Coadministration may decrease glasdegib plasma concentrations, thereby reducing efficacy
            • Prolonged QTc
              • Associated with concentration-dependent QTc prolongation
              • Avoid coadministration with QTc prolonging drugs
              • If unavoidable, monitor for increased risk of QTc interval prolongation
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            Pregnancy

            Pregnancy

            Based on its mechanism of action and findings in animal embryo-fetal developmental toxicity studies, glasdegib can cause fetal harm when administered to pregnant women

            Animal studies

            • Exposure 3-4 times that of humans: Resulted in embryo-fetal lethality (eg, increased postimplantation loss and decreased numbers of live fetuses) in rats and rabbits
            • Exposure 0.6 times that of humans: 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

            Infertility

            • Males: Based on findings in repeat-dose animal toxicity studies in rats, may impair fertility in males of reproductive potential; some effects on male reproductive organs did not recover

            Contraception

            • Females of reproductive potential: Use effective contraception during treatment and for at least 30 days after last dose
            • Do not donate blood during treatment and for at least 30 days after last dose
            • Males
              • Unknown if 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 for at least 30 days after last dose
              • Advise males to not donate sperm or blood during treatment and for at least 30 days after last dose

            Lactation

            • No data are available on the presence in human milk, effects on the breastfed child, or effect on milk production
            • Advise women not to breastfeed or provide breast milk to infants or children during treatment and for at least 30 days after last dose

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Inhibits the smoothen (SMO) receptor, a transmembrane protein involved in hedgehog (Hh) signal transduction, thereby disrupting the Hh pathway

            SMO inhibition of Hh signaling impacts tumor biology by disrupting the regulation of cancer stem cell survival; this may inhibit development of drug resistance and prevent relapse

            Absorption

            Bioavailability: 77%

            Peak plasma time: 1.3-1.8 hr

            Peak plasma concentration: 1,252 ng/mL

            AUC: 17,210 ng·hr/mL

            Steady-state: Achieved by 8 days of daily dosing

            Effect of food: High-fat, high-calorie meal reduced glasdegib’s AUC (16%) and peak plasma concentration (31%)

            Distribution

            Protein bound: 91%

            Vd: 188 L

            Metabolism

            Primary metabolic pathway: CYP3A4

            Minor metabolic pathways: CYP2C8 and UGT1A9

            Elimination

            Half-life: 17.4 hr

            Clearance: 6.45 L/hr

            Excretion: Urine (49% [17% unchanged]); Feces (42% ]20% unchanged])

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            Administration

            Oral Administration

            Administer with or without food

            Swallow tablet whole; do not split or crush

            Administer at about the same time each day

            Missed or vomited dose

            • Vomited dose: Do not replace dose; wait until the next scheduled dose is due
            • Missed dose or not taken at usual time: Administer dose as soon as possible and at least 12 hr before the next scheduled dose; return to normal schedule the following day
            • Do not administer 2 doses within 12 hr

            Storage

            Store at 20-25°C (68-77°F); excursions permitted between 15-30°C (59-86°F)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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