Glasdegib: Dosage, Mechanism of Action/Onset of Action, Half-Life - Medicine.com (2023)

dosage form

Excipients when available (limited, especially for generic drugs); consult the specific product label.

Pills, oral, maleate:

Daurismo: 25 mg, 100 mg

Pharmacology

Mechanism

Glasdegib is a small molecule inhibitor of the Hedgehog pathway. Glasdegib binds to and inhibits Smoothened (SMO), a transmembrane protein involved in hedgehog signaling. Glasdegib blocks SMO translocation to cilia and prevents SMO-mediated activation of downstream Hedgehog targets (Cortes 2018). In animal models of AML, glasdegib (combined with low-dose cytarabine) reduced the percentage of CD45+/CD33+ blasts in the bone marrow and inhibited tumor growth to a greater extent than either drug alone.

Pharmacokinetics/pharmacodynamics

to distribute

188 liters

metabolism

It acts mainly in the liver through CYP3A4, to a lesser extent CYP2C8 and UGT1A9.

excretion

Urine: 49% (17% parent drug); Feces: 42% (20% parent substance)

Rush hour

1.3 to 1.8 hours

elimination half-life

17.4 hours ± 3.7 hours

protein bond

91% human plasma protein

Uses: labeling indications

Acute myeloid leukemia:Treatment of newly diagnosed acute myeloid leukemia (in combination with low dose cytarabine) in adults ≥75 years of age or with comorbidities that preclude intensive induction chemotherapy.

Limitations of Use: Has not been studied in patients with severe renal impairment or moderate to severe hepatic impairment.

contraindications

There are no contraindications listed on the manufacturer's label.

Dosage and administration

Dose: Adult

uses:Confirm the status of pregnancy in women of reproductive potential within 7 days prior to the start of treatment.

Acute myeloid leukemia:Adults ≥75 years or with comorbidities: Oral: 100 mg once daily (in combination with low dose subcutaneous cytarabine) for at least 6 cycles (28 days) (to allow time for clinical response) or until disease progression. unacceptable disease or toxicity

Missed dose or vomited:If a dose is missed, give it as soon as possible and at least 12 hours before the next scheduled dose; resume your normal schedule the next day. Do not take 2 doses within 12 hours. If a dose is vomited, do not give a replacement dose. Resume dosing with the next scheduled dose.

Dose: Geriatric

See adult dosage.

Dose: Adjusted for toxicity

Hematologic Toxicity:

Neutrophils <500/mm³More than 42 days (in the absence of disease):Permanently discontinue glasdegib (and low-dose cytarabine).

Platelets <10,000/mm³More than 42 days (in the absence of disease):Permanently discontinue glasdegib (and low-dose cytarabine).

Non-haematological toxicity:

QTc prolongation (at least 2 separate electrocardiograms [ECGs]):

QTc interval >480 to 500 msec: Evaluate electrolytes and replace as needed; check and adjust concomitant medications with known QTc-prolonging effects. After resolution of QTc prolongation to ≤480 msec. The ECG is checked at least weekly for 2 weeks.

QTc interval >500 ms: Withhold glasdegib treatment. Evaluate electrolytes and supplements as needed; review and adjust concomitant medications with known QTc prolongation effects. Resume glasdegib at a reduced dose of 50 mg once daily when the QTc interval returns to within 30 ms of baseline or ≤480 ms. Monitor ECG at least weekly for 2 weeks after resolution of QTc interval prolongation. If an alternate cause of QTc prolongation is identified, consider increasing the glasdegib dose back to 100 mg once daily.

QTc interval prolongation associated with life-threatening arrhythmias: Permanently discontinue glasdegib.

Other toxicity:

Grade 3: Withhold glasdegib and/or low-dose cytarabine until symptoms decrease to mild or return to baseline. Resume glasdegib at the same or reduced dose of 50 mg (also resume low-dose cytarabine at the same or reduced dose). If toxicity recurs, discontinue glasdegib (and low-dose cytarabine) unless toxicity is due to glasdegib alone.

Grade 4: Permanently discontinue glasdegib (and low-dose cytarabine).

administrative

Oral: Administer with or without food at approximately the same time each day. Do not split or crush the tablet.

storage

Store at 20°C to 25°C (68°F to 77°F); excursions between 15°C and 30°C (59°F to 86°F) are allowed.

drug interactions

Aprepitant: May increase serum concentrations of CYP3A4 substrates (high risk with inhibitors).treatment monitoring

Bosentan: May reduce serum concentrations of CYP3A4 substrates (high risk of inducers).treatment monitoring

Clofazimine: May increase serum concentrations of CYP3A4 substrates (high risk with inhibitors).treatment monitoring

Conivaptan: May increase serum concentrations of CYP3A4 substrates (high risk with inhibitors).avoid combinations

CYP3A4 inducers (moderate): May reduce serum concentrations of CYP3A4 substrates (high risk with inducers).treatment monitoring

CYP3A4 inducers (strong): May reduce Glasdegib serum concentrations.avoid combinations

CYP3A4 inhibitors (moderate): May decrease metabolism of CYP3A4 substrates (high risk with inhibitors).treatment monitoring

CYP3A4 inhibitors (strong): Glasdegib serum concentrations may be increased. Management: Consider alternatives to this combination if possible. If combined use is to be used, monitor closely for signs of QT prolongation and other side effects of glasdegib.Consider adjusting therapy

Dabrafenib: May reduce serum concentrations of CYP3A4 substrates (high risk of inducers). Management: Find alternatives to CYP3A4 substrates when possible. If concomitant treatment cannot be avoided, the clinical effect (especially the therapeutic effect) of the substrate should be closely monitored.Consider adjusting therapy

Deerasirox: May reduce serum concentrations of CYP3A4 substrates (high risk of inducers).treatment monitoring

Duvelisib: May increase serum concentrations of CYP3A4 substrates (high risk with inhibitors).treatment monitoring

Erdafitinib: May reduce serum concentrations of CYP3A4 substrates (high-risk inducers).treatment monitoring

Erdafitinib: May increase serum concentrations of CYP3A4 substrates (high risk of inhibitors).treatment monitoring

Fosaprepitant: May increase serum concentrations of CYP3A4 substrates (high risk with inhibitors).treatment monitoring

Fosnetupitant: May increase serum concentrations of CYP3A4 substrates (high risk with inhibitors).treatment monitoring

Fusidic Acid (Systemic): May increase serum concentrations of CYP3A4 substrates (high risk with inhibitors).avoid combinations

Haloperidol: QT prolonging agents (unknown risk - avoid) may potentiate the QTc prolonging effect of haloperidol.treatment monitoring

Idelalisib: May increase serum concentrations of CYP3A4 substrates (high risk of inhibitors).avoid combinations

Ivosidenib: May reduce serum concentrations of CYP3A4 substrates (high-risk inducers).treatment monitoring

Larotrectinib: May increase serum concentrations of CYP3A4 substrates (high risk with inhibitors).treatment monitoring

Lorlatinib: May reduce serum concentrations of CYP3A4 substrates (high-risk inducers). Management: Avoid concomitant use of lorlatinib and any CYP3A4 substrate, as small decreases in serum concentrations of CYP3A4 substrates may lead to treatment failure and serious clinical consequences.Consider adjusting therapy

MiFEPRIStone: May increase serum concentrations of CYP3A4 substrates (high risk with inhibitors). Treatment: During and 2 weeks after treatment with mifepristone, minimize the dose of CYP3A4 substrates and monitor for increases in concentration/toxicity. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus.Consider adjusting therapy

Netupitant: May increase serum concentrations of CYP3A4 substrates (high risk of inhibitors).treatment monitoring

Palbociclib: May increase serum concentrations of CYP3A4 substrates (high risk with inhibitors).treatment monitoring

QT-prolonging agents (higher risk): QT-prolonging agents (uncertain risk - avoid) may potentiate the QTc-prolonging effect of QT-prolonging agents (higher risk). Management: Manage QTc interval prolongation and ventricular arrhythmias when these drugs are used in combination. Patients with additional risk factors for QTc interval prolongation may be at increased risk.treatment monitoring

Sarilumab: May reduce serum concentrations of CYP3A4 substrates (high-risk inducers).treatment monitoring

Siltuximab: May reduce serum concentrations of CYP3A4 substrates (high-risk inducers).treatment monitoring

Simeprevir: May increase serum concentrations of CYP3A4 substrates (high risk of inhibitors).treatment monitoring

Stiripentol: May increase serum concentrations of CYP3A4 substrates (high risk of inhibitors). Management: Avoid the use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index due to the increased risk of side effects and toxicity. Any CYP3A4 substrate used with stiripentol requires more stringent control.Consider adjusting therapy

Tocilizumab: May reduce serum concentrations of CYP3A4 substrates (high-risk inducers).treatment monitoring

Side effects

>10%:

Cardiovascular: edema (30%), atrial arrhythmia (13%), chest pain (12%)

Central Nervous System: Fatigue (36%), dizziness (18%), headache (12%)

Dermatology: Rash (20%)

Endocrinology and Metabolism: Hyponatremia (11% to 54%), hypomagnesemia (33%), hyperkalemia (16%), hypokalemia (15%), weight loss (13%)

Gastrointestinal: nausea (29%), decreased appetite (21%), dysgeusia (21%), mucositis (21%; grade ≥3: 1%), constipation (20%), abdominal pain (19%), diarrhea ( 18%) ), vomiting (18%)

Hematology and Oncology: Anemia (43%; grade ≥3: 41%), bleeding (36%; grade ≥3: 6%), febrile neutropenia (31%; grade ≥3: 31%), thrombocytopenia (30%; grade ≥3) ≥3: 30%), white blood cell count decreased (11%; grade ≥3: 11%)

Liver: serum aspartate aminotransferase increased (28%), serum bilirubin increased (25%), serum alanine aminotransferase increased (24%), serum alkaline phosphatase increased (23%)

Neuromuscular and skeletal: musculoskeletal pain (30%), blood test creatine phosphokinase increased (16%), muscle cramps (15%)

Renal: elevated serum creatinine (96%), renal failure (19%)

Respiratory: Dyspnea (23%), pneumonia (19%), cough (18%)

Miscellaneous: Fever (18%)

1% a 10%:

Cardiovascular: ECG QT interval prolongation (4% to 5%)

Infection: sepsis (7%)

Frequency not defined: Endocrine and metabolic: Hypophosphataemia

Warnings/Cautions

Questions related to side effects:

• QTc Prolongation: QTc prolongation and ventricular arrhythmias, including ventricular fibrillation and ventricular tachycardia, may occur. A small proportion of patients in clinical trials had a QTc interval >500 msec; some patients had an increase of >60 ms from baseline. Patients with baseline QTc >470 msec (or with a history of long QT syndrome or uncontrolled cardiovascular disease) were excluded from clinical trials. Concomitant use of drugs that prolong the QTc interval and CYP3A4 inhibitors may increase the risk of QTc prolongation. Monitor electrocardiogram (ECG) and electrolytes; More frequent ECG monitoring may be required in patients with congenital long QT syndrome, heart failure, electrolyte abnormalities, or concomitant medications known to prolong the QTc interval. QTc prolongation may require treatment interruption, dose reduction and/or permanent discontinuation.

Concomitant medication problems:

• DRUG INTERACTIONS: There may be a potentially significant interaction that requires dose or frequency adjustment, additional monitoring, and/or selection of alternative treatment. See the Drug Interaction Database for more details.

Special population:

• Pregnancy: Glasdegib is not recommended for pregnant women.[US Boxed Warning]: Glasdegib may cause embryofoetal death or severe birth defects when taken by a pregnant woman. Glasdegib is embryotoxic, fetotoxic, and teratogenic in animals. Perform a pregnancy test in women of childbearing potential prior to initiating glasdegib treatment. Advise females of reproductive potential to use effective contraception during treatment with glasdegib and for at least 30 days after the last dose of glasdegib. Advise men about the potential risk of exposure to glasdegib through semen, and to use condoms with a pregnant partner or woman of reproductive potential (including after vasectomy) during treatment with glasdegib and for at least 30 days after treatment. the last dose of glasdegib to avoid exposure to the potential drug hazard.

Additional Warnings/Precautions:

• Blood Donation: Advise patients not to donate blood or blood products during treatment with glasdegib and for at least 30 days after the last dose of glasdegib.
• Sperm Donation: Advise patients not to donate sperm during treatment with glasdegib and for at least 30 days after the last dose of glasdegib.

monitoring parameters

Check complete blood count, electrolytes, renal and liver function before treatment, at least weekly for the first month; monitor electrolytes and renal function monthly during treatment (or as clinically indicated); obtain prior to initiation of treatment and as clinically indicated Serum creatine kinase level; pregnancy test (within 7 days prior to initiation of glasdegib treatment in women of childbearing potential); ECG monitoring before starting treatment, approx. 1 week after start, then monthly for the next 2 months; More frequent monitoring (repeat ECG if abnormal) may be required. Monitor compliance.

pregnant

Precautions for pregnancy

Glasdegib is not recommended for pregnant women.[US Boxed Warning] Glasdegib may cause embryofoetal death or severe birth defects when administered to a pregnant woman. Glasdegib is embryotoxic, fetotoxic, and teratogenic in animals.Glasdegib inhibits the Hedgehog pathway, which is essential for fetal development (Walterhouse 1999).

[US Boxed Warning] Prior to initiating glasdegib treatment, perform a pregnancy test in women of reproductive potential.A pregnancy test should be performed within 7 days before starting treatment with glasdegib.Advise females of reproductive potential to use effective contraception during treatment with glasdegib and for at least 30 days after the last dose of glasdegib. Advise men about the potential risk of exposure to glasdegib through semen, and to use condoms with a pregnant partner or woman of reproductive potential (including after vasectomy) during treatment with glasdegib and for at least 30 days after treatment. the last dose of glasdegib to avoid exposure to the potential drug hazard.Semen should not be donated during treatment and for at least 30 days after the last dose of glasdegib. Based on animal data, effective preservation of fertility in males should be considered prior to treatment.

Health care providers are encouraged to register women who are inadvertently exposed to glasdegib during pregnancy with the Pfizer Pregnancy Registry (800-438-1985).

patient education

• Discuss the specific uses and side effects of the medication along with the treatment with the patient. (HCAHPS: During this hospital stay, did you take any medications you had not taken before? Before giving you a new medication, how often did hospital staff tell you what the medication was for? How often did hospital staff describe possible side effects? in a way that you can understand?)
• Patients may experience nausea, vomiting, loss of appetite, stomach pain, constipation, diarrhea, taste disturbance, hair loss, back pain, bone pain, joint pain, muscle pain, neck pain, sores on the mouth, mouth pain or irritation, gum pain and irritation. , weight loss, muscle cramps or headache. Ask patients to report signs of bleeding (spitting up blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding gums; abnormal vaginal bleeding; unexplained or increasing bruising; or persistent bleeding), signs of kidney problems (inability to urinate, blood in the urine, change in the amount of urine, or weight gain), signs of electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heart rhythm , cramps, loss of appetite, or severe nausea or vomiting), dizziness, fainting, fast heartbeat, slow heartbeat, abnormal heartbeat, chest pain, severe loss of strength and energy, chills, sore throat, cough, difficulty breathing or edema (HCAHPS) .
• Teach patients about the signs of a significant reaction (eg, wheezing, chest tightness, fever, itching, severe cough, bluish skin, seizures, or swelling of the face, lips, tongue, or throat) .uses:This is not a complete list of all side effects. Patients should consult their prescribing physician if they have additional questions.

Intended use and disclaimer: Should not be prescribed to patients. This information is intended as a concise introductory reference that healthcare professionals can use when discussing medications with patients. Ultimately, you must rely on your own judgment, experience, and judgment when diagnosing, treating, and counseling patients.