52/18. Glasdegib- (DAURISMO)- (Nov 2018)- to treat newly diagnosed acute myeloid(AML) in adult patients
Drug Name:52/18. Glasdegib- (DAURISMO)- (Nov 2018)- to treat newly diagnosed acute myeloid(AML) in adult patients
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Contra-Indications
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS Table 4. 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 CYP3A Inducers Clinical Impact Co-administration of DAURISMO with strong CYP3A inducers decreased glasdegib plasma concentrations [see Clinical Pharmacology (12.3)]. Prevention or Management Avoid co-administration of DAURISMO with strong CYP3A4 inducers. 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)].
Indication:
U.S. FDA APPROVED DRUGS DURING 2018
Sr.No- 52
Contra-Indications:
--------------------- DOSAGE FORMS AND STRENGTHS --------------------- Tablets: 100 mg, 25 mg. (3) ------------------------------ CONTRAINDICATIONS ------------------------------ None. (4) ----------------------- 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) ------------------------------ ADVERSE REACTIONS ------------------------------ 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. ------------------------------DRUG INTERACTIONS------------------------------- ? Strong CYP3A4 Inhibitors: Consider alternative therapies that are not strong CYP3A inhibitors or monitor for increased risk of adverse reactions, including QTc interval prolongation. (7) ? Strong CYP3A4 Inducers: Avoid concomitant use with DAURISMO. (7) ? QTc Prolonging Drugs: Avoid co-administration with DAURISMO. If co-administration is unavoidable, monitor for increased risk of QTc interval prolongation. (7) ----------------------- USE IN SPECIFIC POPULATIONS ----------------------- ? Lactation: Advise women not to breastfeed. (8.2)
Patient Information:
PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Advise patients of the risks of DAURISMO treatment: 16 Reference ID: 4353045 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 [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)]. 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 [see Use in Specific Populations (8.3)]. Semen Donation ? Advise males not to donate semen during treatment with DAURISMO and for at least 30 days after the last dose of DAURISMO[see Use in Specific Populations (8.3)]. Lactation ? Advise women not to breastfeed during treatment with DAURISMO and for at least 30 days after the last dose of DAURISMO [see Use in Specific Populations (8.2)]. 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 [see Warnings and Precautions (5.1)]. 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 [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)]. 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 [see Warnings and Precautions (5.2)]. This product’s label may have been updated. \
\For current full prescribing information, please visit www.DAURISMO.com. LAB-1284-0.6 17 Reference ID: 435304
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY 12.1 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. 12.2 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. 12.3 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 (AUCtau). 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 AUCtau 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 800-1000 calories: 500-600 fat calories, 250 carbohydrate calories and 150 protein calories) reduced area under the curve over time to infinity (AUCinf) 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. 12 Reference ID: 4353045 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. 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. 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 1-1.5 x ULN and any AST) or mild to moderate renal impairment (creatinine clearance [CLcr] 30-89 mL/min) did not have clinically meaningful effects on the pharmacokinetics of glasdegib. The effect of moderate (total bilirubin 1.5-3 x ULN and any AST) and severe (total bilirubin > 3 x ULN and any AST) hepatic impairment or severe renal impairment (CLcr 15-29 mL/min) on glasdegib pharmacokinetics is unknown. Drug Interaction Studies Clinical Studies Effect of Strong CYP3A4 Inhibitors on Glasdegib: Coadminstration of ketoconazole (a strong inhibitor of CYP3A4) with DAURISMO increased the glasdegib AUCinf by 2.4-fold and Cmax by 1.4-fold over glasdegib given alone [see Drug Interactions (7)]. Effect of Strong CYP3A4 Inducers on Glasdegib: Coadminstration of rifampin (a strong inducer of CYP3A4) with DAURISMO decreased glasdegib AUCinf by 70% and Cmax by 35% [see Drug Interactions (7)]. Effect of Gastric Acid Reducing Agents on Glasdegib: Coadministration of rabeprazole (a proton pump inhibitor) with DAURISMO did not alter glasdegib AUCinf 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. 1
Pregnancy and lactation:
DRUG INTERACTIONS Table 4. 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 CYP3A Inducers Clinical Impact Co-administration of DAURISMO with strong CYP3A inducers decreased glasdegib plasma concentrations [see Clinical Pharmacology (12.3)]. Prevention or Management Avoid co-administration of DAURISMO with strong CYP3A4 inducers. 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)].
8 USE IN SPECIFIC POPULATIONS 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 9 Reference ID: 4353045 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 Cmax (rat) and AUC (rabbit)]. Doses of = 10 mg/kg in rat [approximately 0.6-times the human exposure (Cmax) 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. 8.2 Lactation Risk Summary 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. 8.3 Females and Males of Reproductive Potential DAURISMO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Pregnancy Testing 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 [see Nonclinical Toxicology (13.1)]. 10 Reference ID: 4353045 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 [see Nonclinical Toxicology (13.1)]. Men should seek advice on effective fertility preservation before treatment. 8.4 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. 8.5 Geriatric 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. 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 events reported were nausea, vomiting, dehydration, fatigue and dizziness.
11 DESCRIPTION DAURISMO (glasdegib) is a potent small molecule inhibitor of Smoothened (SMO) for oral use. It is formulated with the maleate salt of glasdegib. The molecular formula for glasdegib maleate is C25H26N6O5. 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 stru