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Glasdegib

FDA Drug Information • Also known as: Daurismo

Brand Names
Daurismo
Drug Class
Hedgehog Pathway Inhibitor [EPC]
Route
ORAL
Dosage Form
TABLET, FILM COATED
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

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 [see Warnings and Precautions (5.1) , Use in Specific Populations (8.1) ] . 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 [see Warnings and Precautions (5.1) , Use in Specific Populations (8.1 , 8.3) ] . 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 [see Warnings and Precautions (5.1) , Use in Specific Populations (8.3) ] . WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning.

  • DAURISMO can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. DAURISMO is embryotoxic, fetotoxic, and teratogenic in animals. ( 5.1 , 8.1 )
  • 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. ( 5.1 , 8.1 , 8.3 )
  • 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 DAURISMO and for at least 30 days after the last dose to avoid potential drug exposure. ( 5.1 , 8.3 )

    • Description

    11 DESCRIPTION DAURISMO (glasdegib) is a hedgehog pathway inhibitor. It is formulated with the maleate salt of glasdegib. The molecular formula for glasdegib maleate is C 25 H 26 N 6 O 5 . The molecular weight for glasdegib maleate is 490.51 Daltons. The chemical name of glasdegib maleate is 1-((2R,4R)-2-(1H-benzo[d]imidazol-2-yl)-1-methylpiperidin-4-yl)-3-(4-cyanophenyl) urea maleate. The molecular structure is shown below: Glasdegib maleate is a white to pale colored powder with pKa values of 1.7 and 6.1. The aqueous solubility of glasdegib maleate is 1.7 mg/mL. DAURISMO (glasdegib) is supplied as a film-coated tablet for oral use containing either 100 mg glasdegib (equivalent to 131.1 mg glasdegib maleate) or 25 mg of glasdegib (equivalent to 32.8 mg glasdegib maleate) together with microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate as inactive ingredients in the tablet. The film-coating consists of Opadry II ® Beige (33G170003) and Opadry II ® Yellow (33G120011) containing: hypromellose, titanium dioxide, lactose monohydrate, macrogol, triacetin, iron oxide yellow, and iron oxide red. Chemical Structure

    What Is Glasdegib Used For?

    1 INDICATIONS AND USAGE DAURISMO is 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. 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. ( 1 )

    Dosage and Administration

    2 DOSAGE AND ADMINISTRATION Recommended dosage: 100 mg orally once daily. ( 2.1 ) 2.1 Recommended Dosage and Schedule The recommended dosage of DAURISMO is 100 mg 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. For patients without unacceptable toxicity, treat for a minimum of 6 cycles to allow time for clinical response. Administer DAURISMO with or without food. Do not split or crush DAURISMO tablets. Administer DAURISMO about the same time each day. If a dose of DAURISMO is vomited, do not administer a replacement dose; wait until the next scheduled dose is due. If a dose of DAURISMO is missed or not taken at the usual time, 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 of DAURISMO within 12 hours. 2.2 Monitoring and Dosage Modifications Assess complete blood counts, electrolytes, renal, and hepatic function prior to the initiation of DAURISMO and at least once weekly for the first month. Monitor electrolytes and renal function once monthly for the duration of therapy. Obtain creatine phosphokinase (CPK) levels prior to initiating DAURISMO and as indicated clinically thereafter (e.g., if muscle symptoms are reported). Monitor electrocardiograms (ECGs) prior to the initiation of DAURISMO, approximately one week after initiation, and then once monthly for the next two months to assess for QTc prolongation. Repeat ECG if abnormal. Certain patients may require more frequent and ongoing ECG monitoring [see Warnings and Precautions (5.2) ]. Manage any abnormalities promptly [see Adverse Reactions (6.1) ]. See Table 1 for dosage modification guidelines for patients who develop an adverse reaction. Table 1. Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Recommended Action Abbreviations: CPK = creatine phosphokinase, ULN = upper limit of normal. QTc interval prolongation on at least 2 separate electrocardiograms (ECGs) [see Warnings and Precautions (5.2) ] QTc interval greater than 480 ms to 500 ms Assess electrolyte levels and supplement as clinically indicated. Review and adjust concomitant medications with known QTc interval-prolonging effects [see Drug Interactions (7) ] . Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation to less than or equal to 480 ms. QTc interval greater than 500 ms Assess electrolyte levels and supplement as clinically indicated. Review and adjust concomitant medications with known QTc interval-prolonging effects [see Drug Interactions (7) ] . Interrupt DAURISMO. Resume DAURISMO at a reduced dosage of 50 mg once daily when QTc interval returns to within 30 ms of baseline or less than or equal to 480 ms. Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation. Consider...

    Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following clinically-significant adverse reactions are described elsewhere in the labeling:

  • QTc Interval Prolongation [see Warnings and Precautions (5.2) ]
  • Musculoskeletal Adverse Reactions [see Warnings and Precautions (5.3) ] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety profile of DAURISMO is based on experience in the BRIGHT AML 1003 study for 111 adults with newly-diagnosed AML and 14 adults with other conditions for which DAURISMO is not indicated [see Clinical Studies (14) ] . Patients were treated with DAURISMO 100 mg daily in combination with low-dose cytarabine (N=84) or low-dose cytarabine alone (N=41). The median duration of treatment in the DAURISMO with low-dose cytarabine arm was 83 days (range 3 to 972 days), and the median duration of treatment in the low-dose cytarabine alone arm was 47 days (range 6 to 239 days). The median exposure to DAURISMO in the DAURISMO with low-dose cytarabine arm was 76 days (range 3 to 954 days). Thirty-two patients (38%) were treated with DAURISMO with low-dose cytarabine for at least 6 months and 14 patients (17%) were treated for at least 1 year. Serious adverse reactions were reported in 79% of patients treated in the DAURISMO with low-dose cytarabine arm. The most common (≥5%) serious adverse reactions in patients receiving DAURISMO with low-dose cytarabine were febrile neutropenia (29%), pneumonia (23%), hemorrhage (12%), anemia (7%), and sepsis (7%). Dose reductions associated with adverse reactions were reported in 26% of patients treated with DAURISMO with low-dose cytarabine, and the most common reasons (≥2%) for dose reductions due to adverse reactions were muscle spasms (5%), fatigue (4%), febrile neutropenia (4%), anemia (2%), thrombocytopenia (2%), and ECG QT prolonged (2%). Adverse reactions leading to permanent discontinuation were reported in 36% of patients treated with DAURISMO with low-dose cytarabine, and 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%). Adverse reactions reported in the first 90 days of therapy on the BRIGHT AML 1003 study are shown in Table 3. Table 3. Adverse Reactions Occurring in ≥10% of Patients Adverse reactions with ≥10% incidence in the DAURISMO with low-dose cytarabine arm or the low-dose cytarabine arm are included. No Grade 5 events in the DAURISMO with low-dose cytarabine or low-dose cytarabine alone arm. Within the First 90 Days of Therapy in BRIGHT AML 1003 Body System Adverse Reactions DAURISMO With Low-Dose Cytarabine N=84 Low-Dose Cytarabine N=41 All Grades % Grade ≥3 % All Grades % Grade ≥3 % Abbreviations: N = number of patients. Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 19.1. BRIGHT AML 1003 used National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Adverse reactions include events that commenced within 28 days after the last treatment dose. Blood and lymphatic system disorder Anemia 43 41 42 37 Hemorrhage Hemorrhage includes petechiae, epistaxis, hematoma, contusion, rectal hemorrhage, anal hemorrhage, ecchymosis, gingival bleeding, hematuria, mouth hemorrhage, purpura, cerebral hemorrhage, eye contusion, eye...

    • Drug Interactions

    7 DRUG INTERACTIONS Table 5. Drug Interactions with DAURISMO Strong CYP3A Inhibitors Clinical Impact

  • Co-administration of DAURISMO with strong CYP3A inhibitors increased glasdegib plasma concentrations [see Clinical Pharmacology (12.3) ].
  • Increased glasdegib concentrations may increase the risk of adverse reactions including QTc interval prolongation [see Warnings and Precautions (5.2) ] . Prevention or Management
  • Consider alternative therapies that are not strong CYP3A4 inhibitors during treatment with DAURISMO.
  • Monitor patients for increased risk of adverse reactions including QTc interval prolongation [see Warnings and Precautions (5.2) ]. Strong and Moderate CYP3A Inducers Clinical Impact Co-administration of DAURISMO with strong and moderate CYP3A inducers decreased glasdegib plasma concentrations [see Clinical Pharmacology (12.3) ] .
  • Decreased glasdegib concentrations may reduce efficacy. Prevention or Management
  • Avoid co-administration of DAURISMO with strong and moderate CYP3A4 inducers.
  • If co-administration of DAURISMO with moderate CYP3A4 inducers cannot be avoided, increase the dose of DAURISMO [see Dosage and Administration (2.3) ] . QTc Prolonging Drugs Clinical Impact Co-administration of DAURISMO with QTc prolonging drugs may increase the risk of QTc interval prolongation [see Warnings and Precautions (5.2) ]. Prevention or Management
  • 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 [see Warnings and Precautions (5.2) ].
  • Strong CYP3A4 Inhibitors: Consider alternative therapies that are not strong CYP3A4 inhibitors or monitor for increased risk of adverse reactions, including QTc interval prolongation. ( 7 )
  • Strong CYP3A4 Inducers: Avoid concomitant use with DAURISMO. ( 7 )
  • Moderate CYP3A4 Inducers: Avoid concomitant use with DAURISMO. If, concomitant use cannot be avoided, increase the dose of DAURISMO. ( 2.3 , 7 )
  • QTc Prolonging Drugs: Avoid co-administration with DAURISMO. If co-administration is unavoidable, monitor for increased risk of QTc interval prolongation. ( 7 )

    • Contraindications

    4 CONTRAINDICATIONS None. None. ( 4 )

    Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Based on its mechanism of action and findings in animal embryo-fetal developmental toxicity studies, DAURISMO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no clinical data on the use of DAURISMO in pregnant women to inform of a drug-associated risk of major birth defects and miscarriage. DAURISMO is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating treatment with DAURISMO. Report pregnancy exposures to Pfizer at 1-800-438-1985. In animal embryo-fetal developmental toxicity studies, repeat-dose oral administration of DAURISMO 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 (see Data ) . 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. Data 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 C max (rat) and AUC (rabbit)]. Doses of ≥10 mg/kg in rat [approximately 0.6-times the human exposure (C max ) at the recommended dose] and ≥5 mg/kg in...

    Overdosage

    10 OVERDOSAGE There is no specific antidote for DAURISMO. Management of DAURISMO overdose should include symptomatic treatment and ECG monitoring. Glasdegib has been administered in clinical studies up to a dose of 640 mg/day. At the highest dosage, the adverse reactions that were dose limiting were nausea, vomiting, dehydration, hypotension, fatigue, and dizziness.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING DAURISMO is supplied in the following strengths and package configurations: DAURISMO film-coated tablets Package Configuration Tablet Strength (mg) NDC Print (description) 30 count bottle 100 mg 0069-1531-30 100 mg strength: 11 mm round, pale orange film-coated tablet debossed with "Pfizer" on one side and "GLS 100" on the other 60 count bottle 25 mg 0069-0298-60 25 mg strength: 7 mm round, yellow film-coated tablet debossed with "Pfizer" on one side and "GLS 25" on the other Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.