DAURISMO (glasdegib) tablets

DAURISMO (glasdegib) tablets

DAURISMO (glasdegib) tablets

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.

Indications and usage

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.

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.

Dosage and administration

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.

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Contraindications

None

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.

Warnings and precautions

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.

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.

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.

QTc Interval Prolongation: Patients treated with DAURISMO can develop QTc prolongation and ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia. 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.

Drug interactions

Strong CYP3A Inhibitors: Co-administration of DAURISMO with strong CYP3A inhibitors increased glasdegib plasma concentrations.

Increased glasdegib concentrations may increase the risk of adverse reactions including QTc interval prolongation.

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

Strong and Moderate CYP3A Inducers: Co-administration of DAURISMO with strong and moderate CYP3A inducers decreased glasdegib plasma concentrations.

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.

QTc Prolonging Drugs: Co-administration of DAURISMO with QTc prolonging drugs may increase the risk of QTc interval prolongation

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

Use in specific populations

Pregnancy: 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.

Pregnancy Testing: Conduct pregnancy testing in females of reproductive potential within 7 days prior to initiating therapy with DAURISMO.

Lactation: 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.

Infertility: 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.

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.

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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.

Renal Impairment: No dosage modification is recommended for patients with mild to severe renal impairment (estimated glomerular filtration rate [eGFR] 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

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.

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