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

Before starting the treatment, make sure to check if women who can have children are not pregnant within the last 7 days.

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

For adults 75 years and older or those with health issues:

• Take 100 mg of Glasdegib by mouth every day.
• This is combined with a low-dose cytarabine injection under the skin.
• Continue this for at least 6 months (with each month being 28 days long) to see if it's working.
• If the disease gets worse or the side effects are too much, stop the treatment.

If a Dose is Missed or Thrown Up:

• Missed a dose? Take it as soon as you remember. But if your next dose is in less than 12 hours, skip the missed one and go back to your regular schedule the next day. Don't take two doses in a 12-hour span.
• If you throw up a dose, don't take an extra one. Just continue with your next scheduled dose.

Use in Children:

Not indicated.

Glasdegib (Daurismo) Pregnancy Risk Category: N

• Pregnant women should not use Glasdegib. It can cause serious problems for the baby or even death of the baby before birth. It's been found to harm the baby's development in animal tests.
• If you're a woman who could become pregnant, you need to take a pregnancy test before starting Glasdegib. This test should be done within 7 days before starting the treatment.
• If you're taking Glasdegib, you should use effective birth control during the treatment and for at least 30 days after the last dose. This is to avoid getting pregnant while taking the medicine.
• If you're a man and your partner is pregnant or could become pregnant, you should use condoms while taking Glasdegib and for at least 30 days after the last dose. This is to make sure the medicine doesn't affect your partner or potential baby.
• Men shouldn't donate semen while taking Glasdegib and for at least 30 days after the last dose.
• If you're a man and considering having children in the future, talk to your doctor before starting Glasdegib.

Glasdegib can be used during breastfeeding

• We don't know if Glasdegib can be found in breast milk.
• Because there's a chance it might harm a baby who is breastfed, it's advised not to breastfeed while taking this medicine and for at least 30 days after the last dose.

Glasdegib (Daurismo) Dose in Kidney Disease:

• If your kidneys filter 30 to 89 mL of liquid per minute (CrCl 30 to 89 mL/minute): The manufacturer doesn't give any special dosage instructions. Studies show that having mild or moderate kidney problems doesn't really change how Glasdegib works in your body.
• If your kidneys filter less than 30 mL of liquid per minute (CrCl <30 mL/minute): The manufacturer doesn't give any special dosage instructions, mainly because this situation hasn't been studied yet.

Glasdegib (Daurismo) Dose in Liver disease:

• Mild Liver Problems: If the level of bilirubin (a substance made by the liver) is at or below the normal upper limit and the AST (a liver enzyme) is more than the normal limit OR if the bilirubin is between 1 and 1.5 times the upper normal limit with any AST level: The manufacturer doesn't give any special dosage instructions. Studies show that having mild liver problems doesn't really change how Glasdegib works in your body.
• Moderate to Severe Liver Problems: If the bilirubin is between 1.5 to 3 times the upper normal limit or more than 3 times the upper normal limit with any AST level: The manufacturer doesn't give any special dosage instructions, mainly because this situation hasn't been studied yet.

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:

• Glasdegib can cause a heart problem known as QTc prolongation.
• This means the heart might not beat regularly and could lead to dangerous heart rhythms.
• Some of these dangerous rhythms include ventricular fibrillation and ventricular tachycardia.
• In a study, a small number of patients had a significant increase in their QTc interval (a measurement of heart rhythm).
• If a person's QTc was already long (above 470 msec) or they had a history of certain heart issues, they weren't allowed to join the study.
• If someone is taking other medications known to lengthen the QTc interval or certain drugs that affect liver enzymes (CYP3A4 inhibitors), the risk of this heart issue might go up.
• It's important to regularly check heart activity with a test called an ECG, especially if someone has certain heart conditions, imbalanced salt levels in their blood, or is taking other medications that can affect the heart's rhythm.
• Depending on how severe the heart issue is, a doctor might pause Glasdegib treatment, lower the dose, or stop it altogether.

Glasdegib: Drug Interaction

Monitoring parameters:

Before Starting Therapy:

• Check blood counts.
• Measure salt levels in the blood (electrolytes).
• Test kidney and liver function.
• For women who can become pregnant: Take a pregnancy test (within 7 days before starting Glasdegib).
• Check heart activity with an ECG (electrocardiogram).
• Measure a blood marker called serum creatine kinase.

First Month of Therapy:

• Every week:
  • Check blood counts.
  • Test kidney and liver function.
  • Measure salt levels in the blood.

Ongoing Therapy (Each Month):

• Measure salt levels in the blood.
• Test kidney function.

Monitoring the Heart:

• About 1 week after starting therapy: Check heart activity with an ECG.
• For the next 2 months: Do a monthly ECG.
• If an ECG shows something unusual: Do another ECG soon after.

General:

• Keep an eye on whether the patient is taking the medication regularly (monitor adherence).

How to administer Glasdegib (Daurismo)?

• Can be taken with or without food.
• Try to take it at the same time every day.
• Don't break or crush the tablets.

Mechanism of action of Glasdegib (Daurismo):

• Glasdegib is a small molecule that blocks a pathway in the body called the Hedgehog pathway.
• It works by sticking to a protein called Smoothened (SMO), which is part of this pathway.
• The Hedgehog pathway is involved in sending signals within cells.
• Glasdegib stops SMO from moving to specific parts of cells called cilia, and this prevents SMO from activating certain signals that are part of the Hedgehog pathway.
• This action affects the way cells communicate and respond to signals.

Combination Treatment in Animal AML Model:

• In a test involving animals with acute myeloid leukemia (AML), glasdegib was used along with low-dose cytarabine (a type of chemotherapy).
• This combination treatment reduced the number of specific cells (CD45+/CD33+ blasts) in the bone marrow.
• It also stopped tumor size from getting bigger more effectively than using either treatment on its own.

Distribution:

• Glasdegib spreads out in the body to a volume of 188 liters.

Binding in the Blood:

• 91% of Glasdegib attaches to proteins in human blood.

How the Body Processes It (Metabolism):

• The liver mainly processes Glasdegib, using an enzyme called CYP3A4.
• There's a bit of processing by two other enzymes, CYP2C8 and UGT1A9.

How Much Gets Into the Bloodstream (Bioavailability):

• 77% of the taken Glasdegib actually reaches the bloodstream.

How Long It Stays in the Body (Half-life):

• It takes about 17.4 hours (plus or minus 3.7 hours) for half of Glasdegib to be cleared from the body.

How Quickly It Peaks in the Blood:

• Glasdegib reaches its highest level in the blood between 1.3 to 1.8 hours after being taken.

How It Leaves the Body (Excretion):

• Urine: About 49% of Glasdegib exits the body through urine, with 17% of it being the unchanged drug.
• Feces: About 42% of Glasdegib is excreted in feces, with 20% of it being the unchanged drug.

International Brand Names of Glasdegib:

• Daurismo

Glasdegib Brand Names in Pakistan:

Not available.