Daurismo

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 )

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 re-escalating the dosage of DAURISMO to 100 mg daily if an alternative etiology for the QTc prolongation can be identified. QTc interval prolongation with life-threatening arrhythmia Discontinue DAURISMO permanently. Musculoskeletal adverse reactions [see Warnings and Precautions (5.3) ] Grade 3 Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. or serum CPK elevation between 2.5 and 10 times upper limit of normal (ULN) Obtain CPK and serum creatinine levels at least weekly until resolution of clinical signs and symptoms. Interrupt DAURISMO until symptoms reduce to mild or return to baseline. Resume DAURISMO at the same dose level, or at a reduced dose of 50 mg. If toxicity recurs, discontinue DAURISMO. Grade 4 or serum CPK elevation greater than 10 times ULN Discontinue DAURISMO. Hematologic toxicity [see Adverse Reactions (6.1) ] Platelets less than 10 Gi/L for more than 42 days in the absence of disease Discontinue DAURISMO and low-dose cytarabine per…

5 WARNINGS AND PRECAUTIONS • 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. ( 5.1 ) • QTc Interval Prolongation: Monitor electrocardiograms and electrolytes. If QTc prolongation occurs, interrupt treatment with DAURISMO. ( 2.2 , 5.2 ) • Musculoskeletal Adverse Reactions: Obtain creatine phosphokinase (CPK) and serum creatinine levels prior to initiating DAURISMO and as indicated clinically thereafter. Temporary dose interruption, dose reduction, or discontinuation of DAURISMO may be required for musculoskeletal adverse reactions or serum CPK elevation. ( 2.2 , 5.3 ) 5.1 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 [see Use in Specific Populations (8.1 , 8.2) , Clinical Pharmacology (12.1) ] . 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 [see Use in Specific Populations (8.2 , 8.3) ] . 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 [see Use in Specific Populations (8.3) ] . 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. 5.2 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 [see Dosage and Administration (2.2) ] . Concomitant use of DAURISMO with drugs known to prolong the QTc interval and CYP3A4 inhibitors may increase the risk of QTc interval prolongation [see Drug Interactions (7) , Clinical Pharmacology (12.2) ] . 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 [see Dosage and Administration (2.2) ] . 5.3 Musculoskeletal Adverse Reactions Musculoskeletal adverse reactions, which may be accompanied by CPK elevations, have occurred with DAURISMO and other drugs which inhibit the hedgehog (Hh) path…

4 CONTRAINDICATIONS None. None. ( 4 )

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 )

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 rabbit resulted in 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.

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 hemorrha…