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. 

 Strong CYP3A4 Inducers: Avoid concomitant use with DAURISMO. 

 QTc Prolonging Drugs: Avoid co-administration with DAURISMO. If co-administration is unavoidable, monitor for increased risk of QTc interval prolongation. 

U.S. FDA APPROVED  DRUGS DURING 2018

Sr.No-  52

 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.

 CONTRAINDICATIONS                                                                                               None. 

 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. 

 QTc Interval Prolongation: Monitor electrocardiograms and electrolytes. If QTc prolongation occurs, interrupt treatment with DAURISMO. 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

 Advise patients of the risks of DAURISMO treatment: 

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 

Use in Specific Populations 

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 

                         NA

CLINICAL PHARMACOLOGY

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.

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.

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. 

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 

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. 

 USE IN SPECIFIC POPULATIONS

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 

. 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. 

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. 

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.

3. Females and Males of Reproductive Potential

DAURISMO can cause fetal harm when administered to a pregnant woman

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 

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.

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.

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.

 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.