Safety Profile

Adverse events

​​​​​​​The safety profile of DAURISMO + LDAC was established in older patients not eligible for intensive chemotherapy1

Adverse reactions (ARs) occurring in ≥10% of patients* within the first 90 days of therapy1

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   *ARs with ≥10% incidence in the DAURISMO + LDAC arm or the LDAC arm are included. ARs included events that commenced within 28 days after the last treatment dose. ARs were graded according to NCI CTCAE version 4.0.

    NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.

  • Muscle spasms and decreased appetite worsened (ie, progressed from grades ≤2 to grade 3 or higher) after the first 90 days of therapy1
  • Serious ARs were reported in 79% of patients treated in the DAURISMO (glasdegib) + LDAC arm compared with 78% in the LDAC-alone arm1,2
  • The most common (≥5%) serious ARs in patients receiving DAURISMO + LDAC compared with LDAC alone, respectively, were febrile neutropenia (29% vs 17%), pneumonia (23% vs 17%), hemorrhage (12% vs 7%), anemia (7% vs 0%), and sepsis (7% vs 15%)1,2

Laboratory abnormalities

Selected laboratory abnormalities (≥15%) within the first 90 days of therapy in BRIGHT AML 10031

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   †Maximum severity based on the number of patients with available on-study laboratory data.

   ‡Grade 1 is mild, grade 2 is moderate, grade 3 is severe, and grade 4 is life-threatening.

    BRIGHT AML 1003 used NCI CTCAE version 4.0.

  • Laboratory abnormalities that worsened (ie, progressed from grades ≤2 to grade 3 or higher) after the first 90 days of therapy included hypophosphatemia, creatinine increased, and ALT increased1

Discontinuation rates

Permanent discontinuation1

  • ARs leading to permanent discontinuation were reported in 36% of patients in the DAURISMO + LDAC arm
  • The most common (≥2%) reasons for permanent discontinuation were pneumonia (6%), febrile neutropenia (4%), sepsis (4%), sudden death (2%), myocardial infarction (2%), nausea (2%), and renal insufficiency (2%)

Dose reductions

Dose reductions1

  • The DAURISMO dose was reduced due to ARs in 26% of patients
  • The most common (≥2%) ARs reported as the reason for dose reductions were muscle spasms (5%), fatigue (4%), febrile neutropenia (4%), anemia (2%), thrombocytopenia (2%), and electrocardiogram (ECG) QT prolonged (2%)

References:​​​​​​​
  1. Daurismo [Prescribing Information]. New York, NY: Pfizer Inc.; 2020.
  2. Data on file. Pfizer Inc., New York, NY.

Efficacy & Safety

  • Study Design
  • Efficacy
  • Safety Profile
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Study Design

The efficacy and safety of DAURISMO were evaluated in a randomized, Phase 2 study

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Efficacy

The efficacy of DAURISMO + LDAC was established on the basis of overall survival

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Dosing and Drug Interactions

Oral DAURISMO in combination with LDAC offers the potential for treatment at home

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

Blood Donation: Advise patients not to donate blood or blood products while taking DAURISMO and for at least 30 days after the last dose, because their blood or blood products might be given to a female of reproductive potential.

QTc Interval Prolongation: Patients treated with DAURISMO can develop QTc prolongation and ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia. Of the 98 evaluable patients treated with DAURISMO 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. Monitor electrocardiograms (ECGs) and electrolytes. Concomitant use of DAURISMO 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. Interrupt DAURISMO if QTc interval is >500 ms and discontinue permanently for patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

Adverse Reactions: Most common adverse reactions associated with DAURISMO (incidence ≥20%) were anemia (43%), fatigue (36%), hemorrhage (36%), febrile neutropenia (31%), musculoskeletal pain (30%), edema (30%), thrombocytopenia (30%), nausea (29%), dyspnea (23%), decreased appetite (21%), dysgeusia (21%), mucositis (21%), constipation (20%), and rash (20%).

Drug Interactions: Co-administration with strong CYP3A4 inhibitors increased DAURISMO plasma concentrations, which may increase the risk of adverse reactions including QTc interval prolongation. Consider alternative therapies that are not strong CYP3A4 inhibitors during treatment with DAURISMO and monitor patients for increased risk of adverse reactions including QTc interval prolongation. Strong and moderate CYP3A4 inducers should be avoided due to decreased DAURISMO plasma concentrations, which may reduce efficacy. If concomitant use of moderate CYP3A4 inducers cannot be avoided, increase the DAURISMO dosage to 200 mg once daily (if the patient is taking 100 mg) and 100 mg once daily (if the patient is taking 50 mg) as tolerated. Co-administration of DAURISMO with QTc-prolonging drugs may increase the risk of QTc interval prolongation. Avoid co-administration of QTc-prolonging drugs with DAURISMO or replace with alternative therapies. If co-administration of a QTc-prolonging drug is unavoidable, monitor patients for increased risk of QTc interval prolongation.

Lactation: Because of the potential for serious adverse reactions from DAURISMO in a breastfed child, advise women who are taking DAURISMO not to breastfeed or provide breast milk to infants or children during treatment and for at least 30 days after the last dose.

Renal Impairment: No dosage modification is recommended for patients with mild to severe renal impairment. Monitor patients with severe renal impairment (eGFR 15 to 29 mL/min) for increased risk of adverse reactions, including QTc interval prolongation, due to increased glasdegib concentrations.

DAURISMO 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.

Please see full Prescribing Information, including BOXED WARNING and Medication Guide.

Indication

DAURISMOTM 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.