Glasdegib (Daurismo) is a Hedgehog pathway inhibitor that is used in combination with cytarabine to treat acute myeloid leukemia in older adults who have co-morbidities and in whom intensive induction chemotherapy can not be used.

Glasdegib Uses:

• Acute myeloid leukemia:

  • Glasedgib is used in the treatment of newly-diagnosed acute myeloid leukemia (in combination with low-dose cytarabine) in adult patients who are ≥75 years of age or who have comorbidities that preclude the use of intensive induction chemotherapy.
  • Limitation of use: This has not been studied in patients with severe renal impairment or moderate-to-severe hepatic impairment.

Glasdegib (Daurismo) Dose in Adults

Note: Exclude pregnancy status of females of reproductive potential within 7 days prior to therapy initiation.

Glasdegib (Daurismo) Dose in the treatment of Acute myeloid leukemia:

• Adults ≥75 years or with comorbidities:

  • Oral: 100 mg once a day (in combination with subcutaneous low-dose cytarabine) for a minimum of 6 (28-day) cycles (to allow time for clinical response) or until disease progression or unacceptable toxicity.

• Missed or vomited doses:

  • If a dose is missed, administer the dose as soon as possible and at least 12 hours prior to the next scheduled dose.
  • Re-initiate to the normal schedule the following day.
  • Do not administer 2 doses within 12 hours.
  • If a dose is vomited out, do not administer a replacement dose. Resume dosing with the next scheduled dose.

Use in Children:

Not indicated.

Glasdegib (Daurismo) Pregnancy Risk Category: N

• Glasdegib should not be used in pregnant women.
• [US Boxed Warning]Glasdegib can cause severe birth defects or fetal death if given to pregnant women. 
• It can be teratogenic, embryotoxic and fetotoxic in animals. It blocks the Hedgehog pathway, which is crucial for the development of the fetus.
• [US Boxed Warning]Before initiating treatment, it is important to perform pregnancy testing in women of reproductive potential. 
• Within 7 days of starting the treatment, pregnant testing should be done.
• Recommend to all females with reproductive potential that they use effective contraception throughout the treatment and for at most 30 days following the last dose.
• Men should be advised of the possible risk of glasdegib being exposed through their sperm.
• They should also be reminded to use condoms, even after vasectomy, with a partner who is pregnant or has reproductive potential.
• Condoms must be used for at least 30 consecutive days following the last dose in order to prevent drug exposure.
• Sperm should not been donated during treatment or for more than one month following the last dose. According to animal data, men should consider fertility preservation before starting therapy.
• Females accidentally exposed to the drug during pregnancy are encouraged by health care providers to register them to the Pfizer pregnancy registry at 800-438-1985.

Glasdegib can be used during breastfeeding

• It is unknown if the drug is found in breast milk.
• The manufacturer recommends that breastfeeding is stopped during therapy and for no more than 30 days following the last dose.

Glasdegib (Daurismo) Dose in Kidney Disease:

• CrCl 30 to 89 mL/minute:

  • There are no dosage adjustments provided in the manufacturer's labeling.
  • However, mild or moderate renal impairment had no clinically meaningful effect on its pharmacokinetics.

• CrCl <30 mL/minute:

  • There are no dosage adjustments provided in the manufacturer's labeling (it has not been studied).

Glasdegib (Daurismo) Dose in Liver disease:

• Mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to 1.5 times ULN and any AST) impairment:

  • There are no dosage adjustments provided in the manufacturer's labeling.
  • However, mild liver impairment had no clinically meaningful effect on its pharmacokinetics.

• Moderate (total bilirubin 1.5 to 3 times ULN and any AST) or severe (total bilirubin >3 times ULN and any AST) impairment:

  • There are no dosage adjustments provided in the manufacturer's labeling (though it has not been studied).

Common Side Effects of Glasdegib (Daurismo):

• Cardiovascular:

  • Edema
  • Atrial Arrhythmia
  • Chest Pain

• Central Nervous System:

  • Fatigue
  • Dizziness
  • Headache

• Dermatologic:

  • Skin Rash

• Endocrine & Metabolic:

  • Hyponatremia
  • Hypomagnesemia
  • Hyperkalemia
  • Hypokalemia
  • Weight Loss

• Gastrointestinal:

  • Nausea
  • Decreased Appetite
  • Dysgeusia
  • Mucositis
  • Constipation
  • Abdominal Pain
  • Diarrhea
  • Vomiting

• Hematologic & Oncologic:

  • Anemia
  • Hemorrhage
  • Febrile Neutropenia
  • Thrombocytopenia
  • Decreased White Blood Cell Count

• Hepatic:

  • Increased Serum Aspartate Aminotransferase
  • Increased Serum Bilirubin
  • Increased Serum Alanine Aminotransferase
  • Increased Serum Alkaline Phosphatase

• Neuromuscular & Skeletal:

  • Musculoskeletal Pain
  • Increased Creatine Phosphokinase In Blood Specimen
  • Muscle Spasm

• Renal:

  • Increased Serum Creatinine
  • Renal Insufficiency

• Respiratory:

  • Dyspnea
  • Pneumonia
  • Cough

• Miscellaneous:

  • Fever

Less Common Side Effects of Glasdegib (Daurismo):

• Cardiovascular:

  • Prolonged QT interval on ECG

• Infection:

  • Sepsis

Frequency of side effects not defined:

• Endocrine & metabolic:

  • Hypophosphatemia

Contraindications to Glasdegib (Daurismo):

The manufacturer's labeling does not list any contraindications.

Warnings and precautions

• Extension of QTc:

  • QTc prolongation has been reported as well as ventricular arrhythmias such ventricular fibrillation and ventricular tachycardia.
  • In a small number of clinical trials, QTc intervals exceeding 500 msec were observed in patients. Some patients experienced a QTc interval greater than 60msec higher than the baseline.
  • Patients who had a baseline QTc interval greater than 470 msec or with a history long QT syndrome, uncontrolled cardiovascular disease, or with a history of QTc were excluded from the clinical study.
  • The risk of QTc interstitial prolongation may be increased by concurrent use of drugs that can prolong the QTc interval or CYP3A4 inhibits.
  • Monitor electrocardiograms and serum electrolytes. Patients with congenital long QT syndrome or electrolyte abnormalities and patients in heart failure may need to be monitored more frequently.
  • Treatment interruption, a reduction of the dose and/or permanent discontinuation may be required for QTc interval prolongation.

Glasdegib: Drug Interaction

Monitoring parameters:

• Monitor complete blood counts.
• Electrolytes, Renal function tests, and liver function tests before treatment initiation and at least once a week for the first 30 days.
• Obtain serum creatine kinase levels before treatment initiation and as clinically indicated.
• Pregnancy test (within 7 days prior to starting the treatment in females of reproductive potential).
• Monitor ECGs before treatment initiation, about one week after treatment initiation, and then once monthly for the next two months.
• More frequent monitoring may be necessary (repeat ECG if abnormal). Monitor adherence.

How to administer Glasdegib (Daurismo)?

It is administered orally with or without food at approximately the same time each day. The drug should not be crushed or chewed.

Mechanism of action of Glasdegib (Daurismo):

• Glasdegib, a small-molecule inhibitor of Hedgehog's pathway, is available. 
• It binds to Smoothened, a transmembrane transmembrane protein that is involved in Hedgehog signal transmission, and inhibits it.
• It blocks the translocation of SMO to cilia, which prevents Hedgehog targets from being activated by SMO.
• It reduced the number of CD45+/CD33+ blasts and decreased tumor growth in an animal AML model. Its effects were stronger when combined with low dose cytarabine.

Protein binding:

• 91% to human plasma proteins

Metabolism:

• Primarily hepatic via CYP3A4, with minor contributions by CYP2C8 and UGT1A9

Bioavailability:

• 77%

Half-life elimination:

• 17.4 hours ± 3.7 hours

Time to peak:

• 1.3 to 1.8 hours

Excretion:

• Urine: 49% (17% as unchanged drug);
• Feces: 42% (20% as unchanged drug)

International Brand Names of Glasdegib:

• Daurismo

Glasdegib Brand Names in Pakistan:

No Brands Available in Pakistan.