Glasdegib

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# Black Box Warning

# Overview
Glasdegib is a hedgehog pathway inhibitor indicated, in combination with low-dose cytarabine that is FDA approved 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. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include anemia, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

### ULTOMIRIS is indicated for:
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.

### Dosage Forms And Strengths
- DAURISMO 100 mg tablets: round, pale orange film-coated tablet debossed with "Pfizer" on one side and "GLS 100" on the other.
- DAURISMO 25 mg tablets: round, yellow film-coated tablet debossed with "Pfizer" on one side and "GLS 25" on the other.
- 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.
- 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 serum creatine kinase 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.
- Certain patients may require more frequent and ongoing ECG monitoring.
- Manage any abnormalities promptly

### Dosage Modification for Concomitant Use with Moderate CYP3A4 Inducers
- Avoid concomitant use of DAURISMO with moderate CYP3A4 inducers. If concomitant use of moderate CYP3A4 inducers cannot be avoided, increase the DAURISMO dosage as tolerated as shown in Table 2. After the moderate CYP3A4 inducer has been discontinued for 7 days, resume the DAURISMO dose taken prior to initiating the moderate CYP3A4 inducer.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding DAURISMO Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding DAURISMO Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding DAURISMO FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding DAURISMO Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding DAURISMO Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
None

# Warnings

### Embryo-Fetal Toxicity
- Based on its mechanism of action and findings from animal embryo-fetal developmental toxicity studies, DAURISMO can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. There are no clinical data on the use of DAURISMO in pregnant women.
- In animal embryo-fetal developmental toxicity studies, glasdegib caused embryotoxicity, fetotoxicity and teratogenicity at maternal exposures that were less than the human exposure at the recommended human dose of 100 mg. Advise pregnant women of the potential risk to the fetus.

### Females of Reproductive Potential
DAURISMO is not recommended for use during pregnancy. Conduct pregnancy testing in female patients of reproductive potential prior to initiating 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 women not to breastfeed during treatment with DAURISMO and for at least 30 days after the last dose.

### Males
Advise male patients with female partners of the potential risk of exposure through semen and to use effective contraception, including a condom, even after vasectomy, to avoid drug exposure to a pregnant partner or a female partner of reproductive potential during treatment with DAURISMO and for at least 30 days after the last dose.

### Blood Donation
Advise patients not to donate blood or blood products while taking DAURISMO and for at least 30 days after the last dose of DAURISMO 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.
- 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 increases to greater than 500 ms. Discontinue DAURISMO permanently for patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia.

# Adverse Reactions

## Clinical Trials Experience
- 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.
- 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).
- 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%).
- 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%).
- The adverse reactions muscle spasms (4 in 12 patients) and decreased appetite (2 in 10 patients) worsened (i.e. progressed from Grades  2 to Grade 3 or higher) after the first 90 days of therapy in BRIGHT AML 1003.
- Additional clinically-significant adverse reactions occurring in < 10% of patients treated with DAURISMO and low-dose cytarabine in BRIGHT AML 1003 include:
Dental disorders: loose tooth and toothache
Skin and subcutaneous tissue disorders: alopecia
Cardiac disorders: QT interval prolonged
- Dental disorders: loose tooth and toothache
- Skin and subcutaneous tissue disorders: alopecia
- Cardiac disorders: QT interval prolonged
- The following laboratory abnormalities worsened (i.e. progressed from Grades  2 to Grade 3 or higher) after the first 90 days of therapy in BRIGHT AML 1003:
hypophosphatemia (8 in 38 patients), creatinine increased (2 in 39 patients), and ALT increased (2 in 40 patients).
- hypophosphatemia (8 in 38 patients), creatinine increased (2 in 39 patients), and ALT increased (2 in 40 patients).

## Postmarketing Experience
There is limited information regarding Daurismo Postmarketing Experience in the drug label.

# Drug Interactions

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- 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. 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.
- 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.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glasdegib in women who are pregnant.

### Labor and Delivery
The safety and effectiveness of DAURISMO during labor and delivery have not been evaluated.

### Nursing Mothers
There are no data on the presence of glasdegib or its active metabolites in human milk, the effects of the drug on the breastfed child, or its effect on milk production. Because of the potential for serious adverse reactions in a breastfed child from DAURISMO, advise women who are taking DAURISMO not to breastfeed or provide breast milk to infants or children during treatment with DAURISMO and for at least 30 days after the last dose.

### Pediatric Use
The safety and effectiveness of DAURISMO have not been established in pediatric patients. In repeat-dose toxicity studies in rats, oral administration of DAURISMO resulted in adverse changes in growing bone, teeth, and testis. Effects on bone consisted of partial to complete closure of the epiphyseal plate. Effects in growing incisor teeth included degeneration/necrosis of ameloblasts, and complete tooth loss with oral ulceration. Reproductive tissue toxicity was evidenced by testicular degeneration and hypospermatogenesis. These effects in bone, teeth and testis were observed after administration of DAURISMO for 26 weeks at greater than or equal to 50 mg/kg/day corresponding to approximately 6.6-times the steady state AUC in patients at the recommended human dose.

### Geriatic Use
Of the total number of subjects in clinical studies of DAURISMO with low-dose cytarabine (N=88), 98% of the patients were age 65 years or older and 60% of the patients were age 75 years or older. There were insufficient patients younger than age 65 years to determine differences in adverse reactions reported from patients older than 65.

### Gender
There is no FDA guidance on the use of DAURISMO with respect to specific gender populations.

### Race
There is no FDA guidance on the use of DAURISMO with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of DAURISMO in patients with renal impairment.

### Hepatic Impairment
No dosage modification is recommended for patients with mild to severe renal impairment (estimated glomerular filtration rate  15 to 89 mL/min). 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.

### Females of Reproductive Potential and Males
Conduct pregnancy testing in females of reproductive potential within 7 days prior to initiating therapy with DAURISMO.

### Contraception
- Females: Advise females of reproductive potential to use effective contraception during treatment with DAURISMO and at least 30 days after the last dose.
- Males: It is not known if glasdegib is 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 with DAURISMO and for at least 30 days after the last dose. Advise males to not donate semen during treatment with DAURISMO for at least 30 days after the last dose.

### Infertility
Males: Based on findings in repeat-dose animal toxicity studies in rats, DAURISMO may impair fertility in males of reproductive potential. Some effects on male reproductive organs did not recover. Men should seek advice on effective fertility preservation before treatment.

### Immunocompromised Patients
There is no FDA guidance one the use of DAURISMO in patients who are immunocompromised.

# Administration and Monitoring

### Administration

### Recommended Dosage and Schedule
Recommended dosage: 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.

### 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 serum creatine kinase 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.

### Dosage Modification for Concomitant Use with Moderate CYP3A4 Inducers
- Avoid concomitant use of DAURISMO with moderate CYP3A4 inducers.
- If concomitant use of moderate CYP3A4 inducers cannot be avoided, increase the DAURISMO dosage as tolerated.
- After the moderate CYP3A4 inducer has been discontinued for 7 days, resume the DAURISMO dose taken prior to initiating the moderate CYP3A4 inducer.

### Monitoring
There is limited information regarding Glasdegib Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Glasdegib and IV administrations.

# 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.

# Pharmacology

## Mechanism of Action
- Glasdegib is an inhibitor of the Hedgehog pathway.
- Glasdegib binds to and inhibits Smoothened, a transmembrane protein involved in hedgehog signal transduction.
- In a murine xenotransplant model of human AML, glasdegib in combination with low-dose cytarabine, inhibited increases in tumor size and reduced the percentage of CD45+/CD33+ blasts in the marrow to a greater extent than glasdegib or low-dose cytarabine alone.

## Structure
There is limited information regarding DAURISMO Structure in the drug label.

## Pharmacodynamics

### Cardiac Electrophysiology
- The effect of glasdegib administration on corrected QT interval (QTc) was evaluated in a randomized, single-dose, double-blind, 4-way crossover, placebo- and open-label moxifloxacin-controlled study in 36 healthy subjects.
- At therapeutic plasma concentrations for the recommended dose, achieved with a single dose of 150 mg DAURISMO, the largest placebo and baseline-adjusted QTc interval change was 8 ms (90% CI: 6, 10 ms).
- At a two-fold therapeutic plasma concentration, achieved with a single dose of 300 mg DAURISMO, the QTc change was 13 ms (90% CI: 11, 16 ms). Glasdegib is associated with concentration-dependent QTc prolongation.

## Pharmacokinetics
- DAURISMO at 5 mg to 600 mg once daily (0.05 to 6 times the recommended dose) result in a dose proportional increase in glasdegib peak concentrations (Cmax) and area under the curve over the dosing interval (AUC0-Tau).
- Steady-state plasma levels are reached by 8 days of daily dosing.
- The median accumulation ratio of glasdegib ranged from 1.2 to 2.5 following once-daily dosing.
- At DAURISMO 100 mg once daily, the geometric mean (geometric coefficient of variation, % CV) of glasdegib Cmax was 1252 ng/mL (44%) and AUC0-Tau was 17210 ng*hr/mL (54%) in patients with cancer.

### Absorption
- The mean absolute bioavailability of DAURISMO is 77%. Following 100 mg once daily dosing, glasdegib median time to peak concentrations (Tmax) at steady-state ranged from 1.3 hours to 1.8 hours.
- Effect of Food: A high-fat, high-calorie meal (total 8001000 calories: 500600 fat calories, 250 carbohydrate calories and 150 protein calories) reduced area under the curve over time to infinity (AUC0-INF) by 16% and Cmax by 31%.

### Distribution
Glasdegib is 91% bound to human plasma proteins in vitro. The geometric mean (%CV) apparent volume of distribution (Vz/F) was 188 L (20%) in patients with hematologic malignancies.

### Elimination
Glasdegib has a mean ( SD) half-life of 17.4 h (3.7) and geometric mean (%CV) apparent clearance of 6.45 L/h (25%) following 100 mg once daily dosing in patients with hematologic malignancies.
- Metabolism
Glasdegib is primarily metabolized by the CYP3A4 pathway, with minor contributions by CYP2C8 and UGT1A9. Glasdegib accounts for 69% of the total circulating drug related material in plasma.
- Glasdegib is primarily metabolized by the CYP3A4 pathway, with minor contributions by CYP2C8 and UGT1A9. Glasdegib accounts for 69% of the total circulating drug related material in plasma.
- Excretion
Following a single oral dose of 100 mg radiolabeled glasdegib, 49% (17% unchanged) of the administered dose was eliminated in the urine and 42% (20% unchanged) of the administered dose was eliminated in the feces.
- Following a single oral dose of 100 mg radiolabeled glasdegib, 49% (17% unchanged) of the administered dose was eliminated in the urine and 42% (20% unchanged) of the administered dose was eliminated in the feces.

### Specific Populations
Age (25 to 92 years), sex, race (White, Black, Asian), body weight (43.5 to 145.6 kg), mild hepatic impairment (total bilirubin  ULN and AST > ULN or total bilirubin 11.5  ULN and any AST), and mild renal impairment (creatinine clearance 6089 mL/min) did not have clinically meaningful effects on the pharmacokinetics of glasdegib.
- Patients with Renal Impairment
Following administration of a single dose of DAURISMO 100 mg, glasdegib AUC0-INF increased by 2.1-fold in subjects with moderate (eGFR 30 to 59 mL/min) and severe (eGFR 15 to 29 mL/min) renal impairment compared to subjects with normal renal function (eGFR 90 mL/min).
The pharmacokinetics of glasdegib have not been studied in patients with end stage renal disease requiring hemodialysis.
- Following administration of a single dose of DAURISMO 100 mg, glasdegib AUC0-INF increased by 2.1-fold in subjects with moderate (eGFR 30 to 59 mL/min) and severe (eGFR 15 to 29 mL/min) renal impairment compared to subjects with normal renal function (eGFR 90 mL/min).
- The pharmacokinetics of glasdegib have not been studied in patients with end stage renal disease requiring hemodialysis.
- Patients with Hepatic Impairment
Following administration of a single dose of DAURISMO 100 mg, glasdegib AUC0-INF increased by 11% in subjects with moderate hepatic impairment (Child-Pugh B) and decreased by 24% in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function.
- Following administration of a single dose of DAURISMO 100 mg, glasdegib AUC0-INF increased by 11% in subjects with moderate hepatic impairment (Child-Pugh B) and decreased by 24% in subjects with severe hepatic impairment (Child-Pugh C) compared to subjects with normal hepatic function.

### Drug Interaction Studies
- Clinical Studies and Model-Informed Approaches
Effect of Strong CYP3A4 Inhibitors on Glasdegib: Co-administration of ketoconazole (a strong inhibitor of CYP3A4) with DAURISMO increased the glasdegib AUC0-INF by 2.4-fold and Cmax by 1.4-fold over glasdegib given alone.
Effect of Strong and Moderate CYP3A4 Inducers on Glasdegib: Co-administration of rifampin (a strong inducer of CYP3A4) with DAURISMO decreased glasdegib AUC0-INF by 70% and Cmax by 35%. Co-administration of efavirenz (moderate CYP3A4 inducer) is predicted to decrease glasdegib AUC0-INF by 55% and Cmax by 25%.
Effect of Gastric Acid Reducing Agents on Glasdegib: Co-administration of rabeprazole (a proton pump inhibitor) with DAURISMO did not alter glasdegib AUC0-INF but decreased Cmax by 20%.
- Effect of Strong CYP3A4 Inhibitors on Glasdegib: Co-administration of ketoconazole (a strong inhibitor of CYP3A4) with DAURISMO increased the glasdegib AUC0-INF by 2.4-fold and Cmax by 1.4-fold over glasdegib given alone.
- Effect of Strong and Moderate CYP3A4 Inducers on Glasdegib: Co-administration of rifampin (a strong inducer of CYP3A4) with DAURISMO decreased glasdegib AUC0-INF by 70% and Cmax by 35%. Co-administration of efavirenz (moderate CYP3A4 inducer) is predicted to decrease glasdegib AUC0-INF by 55% and Cmax by 25%.
- Effect of Gastric Acid Reducing Agents on Glasdegib: Co-administration of rabeprazole (a proton pump inhibitor) with DAURISMO did not alter glasdegib AUC0-INF but decreased Cmax by 20%.
- In Vitro Studies
Effect of Glasdegib on Cytochrome P450 (CYP) Substrates: Glasdegib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A, and does not induce CYP1A2, CYP2B6, and CYP3A in vitro.
Effect of Transporters on Glasdegib: Glasdegib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
Effect of Glasdegib on Transporters: Glasdegib inhibits P-gp, BCRP, multidrug and toxin extrusion (MATE) protein 1, and MATE-2K, but not organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, and organic cation transporter (OCT)2 in vitro.
- Effect of Glasdegib on Cytochrome P450 (CYP) Substrates: Glasdegib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A, and does not induce CYP1A2, CYP2B6, and CYP3A in vitro.
- Effect of Transporters on Glasdegib: Glasdegib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
- Effect of Glasdegib on Transporters: Glasdegib inhibits P-gp, BCRP, multidrug and toxin extrusion (MATE) protein 1, and MATE-2K, but not organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, and organic cation transporter (OCT)2 in vitro.

## Nonclinical Toxicology

### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity studies have not been performed with glasdegib.
- Glasdegib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro chromosome aberration assay in human lymphocytes. *Glasdegib was not clastogenic or aneugenic in the rat micronucleus assay.
- Based on nonclinical safety findings, glasdegib has the potential to impair reproductive function in males.
Men should seek advice on effective fertility preservation before treatment.
In repeat-dose toxicity studies in rats, findings observed in the male reproductive tract included adverse testicular changes with glasdegib at doses 50 mg/kg/day, and consisted of minimal to severe hypospermatogenesis characterized by partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testicular degeneration did recover. The dose at which testicular effects were observed in male rats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 6.6-times (based on AUC) those associated with the observed human exposure at the 100 mg once daily dose.
- Men should seek advice on effective fertility preservation before treatment.
- In repeat-dose toxicity studies in rats, findings observed in the male reproductive tract included adverse testicular changes with glasdegib at doses 50 mg/kg/day, and consisted of minimal to severe hypospermatogenesis characterized by partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testicular degeneration did recover. The dose at which testicular effects were observed in male rats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 6.6-times (based on AUC) those associated with the observed human exposure at the 100 mg once daily dose.

# Clinical Studies
- The efficacy of DAURISMO in combination with low-dose cytarabine was evaluated in a multicenter, open-label, randomized study (Study BRIGHT AML 1003, NCT01546038) that included 115 patients age 55 years or older with newly-diagnosed AML who met at least one of the following criteria: a) age 75 years, b) severe cardiac disease, c) baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2, or d) baseline serum creatinine >1.3 mg/dL.
- Patients were randomized 2:1 to receive DAURISMO at a 100 mg daily dose with low-dose cytarabine 20 mg subcutaneously twice daily on days 1 to 10 of a 28-day cycle (N=77) or low-dose cytarabine alone (N=38) in 28-day cycles until disease progression or unacceptable toxicity.
- Patients were stratified by cytogenetic risk (good/intermediate or poor).
The two treatment arms were generally balanced with respect to the baseline demographics and disease characteristics
- Efficacy was established on the basis of overall survival (OS) from the date of randomization to death from any cause.
- With a median follow-up of approximately 20 months, the DAURISMO with low-dose cytarabine arm was superior to low-dose cytarabine alone arm.
- Improvement in OS was consistent across prespecified cytogenetic risk subgroups.

# How Supplied

## Storage
Store at 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Medication Guide).

### Embryo-Fetal Toxicity
Advise female patients of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. Advise female patients and female partners of male patients to contact their healthcare provider with a known or suspected pregnancy.

### Females and Males of Reproductive Potential
- 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 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 with DAURISMO and for at least 30 days after the last dose.

### Semen Donation
Advise males not to donate semen during treatment with DAURISMO and for at least 30 days after the last dose of DAURISMO.

### Lactation
Advise women not to breastfeed during treatment with DAURISMO and for at least 30 days after the last dose of DAURISMO.

### Blood Donation
Advise patients not to donate blood or blood products during treatment with DAURISMO and for at least 30 days after the last dose of DAURISMO.

### Infertility
Advise males of reproductive potential of the potential for impaired fertility from DAURISMO. Advise male patients to seek advice on effective fertility preservation before treatment.

### QT Interval Prolongation
Inform patients of signs and symptoms that may be indicative of significant QT interval prolongation. Advise patients to contact their healthcare provider immediately in the event of syncope, pre-syncopal symptoms, and cardiac palpitations.

# Precautions with Alcohol
Alcohol-Glasdegib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
Daurismo

# Look-Alike Drug Names
There is limited information regarding Daurismo Look-Alike Drug Names in the drug label.

# Drug Shortage Status
Drug Shortage

# Price