Glasdegib Maleate – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

Glasdegib is a potent and selective inhibitor of the hedgehog signaling pathway that acts by binding to the smoothened (SMO) receptor. The hedgehog signaling pathway is involved in the maintenance of neural and skin stem cells. In this pathway, the binding of specific ligands to the transmembrane receptor patched (PTCH1) allows the activation of the transcriptional regulators GL11, and GL12, and modulation of the gene expression through SMO-mediated signaling. The aberrant activation of the hedgehog pathway is thought to be implicated in the pathogenesis of chronic myeloid leukemia, medulloblastoma, and basal cell carcinoma due to the hyperproliferative state that a modification of this pathway will produce.

In preclinical studies, glasdegib achieved a significant reduction in leukemic stem cell burden in xenograft models and a reduction in the cell population expressing leukemic stem cell markers. In clinical trials, glasdegib demonstrated a marked downregulation of more than 80% of the expression of glioma-associated transcriptional regulator GL11 in the skin. In this same study, 8% of the studied individuals with acute myeloid leukemia achieved morphological complete remission while 31% achieved a stable disease state. The latest clinical trial proved glasdegib to generate an overall survival of 8.3 months which was almost double what has been observed in patients under low-dose cytarabine treatment. As well, there have been reports of dose-dependent QTc prolongation in patients administered with glasdegib.

Indications

  • Glasdegib, in combination with cytarabine, is indicated for the treatment of newly diagnosed acute myeloid leukemia in adult patients who are over 75 years old or that have co-morbidities that preclude intensive induction chemotherapy. Acute myeloid leukemia is characterized by abnormal production of myeloblasts, red cells, or platelets. It is considered a cancer of the blood and bone marrow and it is the most common type of acute leukemia in adults.
  • Daurismo is indicated, in combination with low-dose cytarabine, for the treatment of newly diagnosed de novo or secondary acute myeloid leukemia (AML) in adult patients who are not candidates for standard induction chemotherapy.
  • Glasdegib is an orally available small molecule inhibitor of the signaling molecule hedgehog which is used as an antineoplastic agent in the treatment of acute myeloid leukemia.
  • Glasdegib, in combination with cytarabine, is indicated for the treatment of newly diagnosed acute myeloid leukemia in adult patients who are over 75 years old or that have co-morbidities that preclude intensive induction chemotherapy.
  • Acute myeloid leukemia is characterized by abnormal production of myeloblasts, red cells, or platelets. It is considered a cancer of the blood and bone marrow and it is the most common type of acute leukemia in adults.[rx]
  • Acute Myeloid Leukemia (AML)

Use in Cancer

Glasdegib maleate is approved to treat:

Glasdegib maleate is also being studied in the treatment of other types of cancer.

Contraindications

  • are allergic to glasdegib or any ingredients of the medication
  • are male and are unwilling or unable to use effective birth control
  • are female, may become pregnant, and are unwilling or unable to use effective birth control
  • are pregnant
  • are breast-feeding
  • Anemia
  • Decreased Blood Platelets
  • Low Levels Of A Type Of White Blood Cell Called Neutrophils
  • Bleeding
  • Stomatitis, A Condition With Painful Swelling And Sores Inside The Mouth
  • Constipation
  • Low Energy
  • Taste Impairment
  • A Skin Rash
  • Visible Water Retention
  • Decreased Appetite
  • Nause
  • Pain In The Muscles Or Bone
  • Low Amount Of Phosphate In The Blood
  • Low Amount Of Sodium In The Blood
  • High Levels Of Potassium In The Blood
  • Low Amount Of Potassium In The Blood
  • Atrial Fibrillation
  • Slow Heartbeat
  • Sinus Tachycardia, A Type Of Fast Heart Rate
  • Prolonged QT Interval On EKG
  • Pneumonia
  • Decreased Kidney Function
  • High Amount Of Bilirubin In The Blood
  • Atrial Arrhythmia, A Type Or Abnormal Heart Beat
  • A Tooth Disease
  • A Toothache
  • Hair Loss
  • Muscle Spasm
  • Dizziness
  • Fever
  • Weight Loss
  • Headache
  • Cough
  • Vomiting
  • Diarrhea
  • Intense Abdominal Pain
  • A Heart Attack
  • Rapid Ventricular Heartbeat
  • Ventricular Fibrillation, A Heart Rhythm Disorder
  • Ventricular Arrhythmias, A Type Of Abnormal Heart Rhythm

Dosage

Strengths: 25 mg; 100 mg

Acute Myeloid Leukemia

  • 100 mg orally once a day on days 1 to 28 in combination with cytarabine 20 mg subcutaneously 2 times a day 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
  • This drug, 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 older or who have comorbidities that preclude the use of intensive induction chemotherapy

Acute Myeloid Leukemia

75 years or older:

  • 100 mg orally once a day on days 1 to 28 in combination with cytarabine 20 mg subcutaneously 2 times a day 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
  • This drug, 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 older or who have comorbidities that preclude use of intensive induction chemotherapy

 Dose Adjustments

Dose Modifications for Adverse Reactions:
QTC INTERVAL PROLONGATION ON AT LEAST 2 SEPARATE ELECTROCARDIOGRAMS (ECGS):

  • QTc interval greater than 480 ms to 500 ms: Assess electrolyte levels as clinically indicated; review and adjust concomitant medications with known QTc interval-prolonging effects; monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation to less than or equal to 480 ms.
  • QTc interval greater than 500 ms: Assess electrolyte levels and supplement as clinically indicated; review and adjust concomitant medications with known QTc interval-prolonging effects; interrupt therapy; resume therapy at a reduced dose of 50 mg once daily when QTc interval returns to within 30 ms of baseline or less than or equal to 480 ms; monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation; consider re-escalating the dose to 100 mg daily if an alternative etiology for the QTc prolongation can be identified.
  • QTc interval prolongation with life-threatening arrhythmia: Permanently discontinue therapy.

HEMATOLOGIC TOXICITY:

  • Platelets less than 10 GI/L for more than 42 days in the absence of disease: Discontinue this drug and low-dose cytarabine permanently.
  • Neutrophil count less than 0.5 GI/L for more than 42 days in the absence of disease: Discontinue this drug and low-dose cytarabine permanently.

NONHEMATOLOGIC TOXICITY:

  • Grade 3: Interrupt this drug and/or low-dose cytarabine until symptoms reduce to mild or return to baseline; resume this drug at the same dose level, or at a reduced dose of 50 mg; resume low-dose cytarabine at the same dose level, or at a reduced dose of 10 or 15 mg; if toxicity recurs, discontinue this drug and low-dose cytarabine; if toxicity is attributable to this drug only, low-dose cytarabine may be continued.
  • Grade 4: Discontinue this drug and low-dose cytarabine permanently.

DOSE MODIFICATION FOR CONCOMITANT USE WITH MODERATE CYP450 3A4 INDUCERS:

  • Avoid concomitant use of this drug with moderate CYP450 3A4 inducers.
  • If concomitant use cannot be avoided, increase the dose of this drug as tolerated as shown below:
  • After the moderate CYP450 3A4 inducer has been discontinued for 7 days, resume this drug at the dose taken prior to initiating the moderate CYP450 3A4 inducer.

DOSE MODIFICATION OF THIS DRUG WHEN TAKEN WITH MODERATE CYP450 INDUCERS:

  • If the current dose is 100 mg once a day: Increase it to 200 mg orally once a day.
  • If the current dose is 50 mg orally once a day: Increase it to 100 mg orally once a day.

Administration advice:

  • This drug may be taken with or without food.
  • Do not split, divide, or crush tablets.
  • Administer at the same time each day.
  • If a dose is vomited, do not administer a replacement dose; wait until the next scheduled dose is due.
  • If a dose 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 within 12 hours.

Side Effects

The Most Common

  • Black, tarry stools
  • bleeding gums
  • blood in the urine or stools
  • chest pain
  • chills
  • confusion
  • cough
  • coughing up blood
  • decreased frequency or amount of urine
  • difficult or labored breathing
  • difficulty in swallowing
  • dizziness or fainting
  • drowsiness
  • dry mouth
  • fainting
  • fast, slow, or irregular heartbeat
  • fever
  • headache
  • increased blood pressure
  • increased menstrual flow or vaginal bleeding
  • increased thirst
  • lightheadedness
  • loss of appetite
  • loss of consciousness
  • lower back or side pain
  • mood or mental changes
  • muscle pain or cramps
  • muscle spasms (tetany) or twitching seizures
  • nausea
  • nervousness
  • nosebleeds
  • numbness or tingling in the hands, feet, or lips
  • painful or difficult urination
  • pale skin
  • paralysis
  • pinpoint red spots on the skin
  • pounding heartbeat
  • prolonged bleeding from cuts
  • rapid, shallow breathing
  • red or black, tarry stools
  • red or dark brown urine
  • seizures
  • sneezing
  • sore throat
  • stomach pain
  • swelling of the face, hands, ankles, or lower legs
  • tightness in the chest
  • trembling
  • troubled breathing with exertion
  • ulcers, sores, or white spots in the mouth
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • vomiting
  • weakness or heaviness of the legs
  • weight gain

More common

  • Bone or muscle pain
  • change in taste
  • constipation
  • cracked lips
  • decreased appetite
  • diarrhea
  • loose tooth
  • loss of taste
  • skin rash
  • thinning or loss of hair
  • toothache
  • changes in sense of taste
  • decreased appetite
  • fatigue
  • hair loss
  • headache
  • muscle, joint, or bone pain
  • muscle spasms or tightness
  • nausea
  • rash
  • sores or pain in the mouth or throat

Rare

  • stomach pain
  • toothache or loose tooth
  • weakness
  • weight loss
  • irregular heartbeat (e.g., fast, slow, or pounding heartbeat; shortness of breath; dizziness)
  • signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
  • signs of clotting problems (e.g., unusual nosebleeds, bruising, blood in urine, coughing blood, bleeding gums, cuts that don’t stop bleeding)
  • signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
  • signs of kidney failure (e.g., decreased urine production, swelling, fatigue, abdominal pain)
  • swelling arms, legs, face
  • symptoms of low sodium levels in the blood (e.g., achy, stiff, or uncoordinated muscles; confusion; tiredness; weakness)
  • symptoms of pneumonia (e.g., fever or chills, shortness of breath, fatigue, chest pain, cough)
  • eye bleeding (e.g., blurred vision, pain when exposed to light, eye bruising)
  • severe breathing problems (respiratory failure: blue color to skin, lips, or fingernails; sleepiness; irregular heartbeat; shortness of breath; loss of consciousness)
  • signs of bleeding in the stomach (e.g., bloody, black, or tarry stools; spitting up of blood; vomiting blood or material that looks like coffee grounds)
  • signs of bleeding in the brain (e.g., sudden or severe headache; sudden loss of coordination; vision changes; sudden slurring of speech; or unexplained weakness, numbness, or pain in arm or leg)
  • signs of a heart attack (e.g., sudden chest pain or pain radiating to back, down arm, jaw; sensation of fullness of the chest; nausea; vomiting; sweating; anxiety)

Drug Interaction

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Drug-Food Interactions

  • Avoid St. John’s Wort. This herb induces CYP3A metabolism and may reduce serum levels of glasdegib.
  • Take at the same time every day.
  • Take with or without food.

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

This medication should not be used during pregnancy, as it may cause harm to the developing baby. If you become pregnant while taking this medication, contact your doctor immediately.

Lactation

It is not known if glasdegib passes into breast milk. Breastfeeding is not recommended while taking this medication. The safety and effectiveness of using this medication have not been established for children.

Precautions

It is very important that your doctor check your progress at regular visits while you are using this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to take it. Blood and urine tests may be needed to check for unwanted effects.

Using this medicine while you are pregnant can harm your unborn baby. It may also cause birth defects if the father is using it when his sexual partner becomes pregnant. Female patients should use effective birth control during treatment with this medicine and for at least 30 days after the last dose. Male patients who have female partners should use effective birth control (even after a vasectomy) during treatment with this medicine and for at least 30 days after the last dose. If you think you have become pregnant while using this medicine, tell your doctor right away.

Your doctor will give you a pregnancy test within 7 days before you use this medicine to make sure you are not pregnant.

Do not donate blood or blood products or sperm while you are using this medicine and for at least 30 days after the last dose.

Contact your doctor right away if you have any changes to your heart rhythm. You might feel dizzy or faint, or you might have a fast, pounding, or uneven heartbeat. Make sure your doctor knows if you had a heart rhythm problem, such as QT prolongation.

If you plan to have children, talk with your doctor before using this medicine. Some men using this medicine have become infertile (unable to have children).

Cancer medicines can cause diarrhea, nausea, vomiting, or stomach pain in most people, sometimes even after receiving medicines to prevent it. Ask your doctor or nurse about other ways to control these unwanted effects.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Before taking this medicine

Glasdegib can cause severe birth defects or death of a baby if the mother or the father is taking this medicine at the time of conception or during pregnancy.

  • If you are a woman who is able to get pregnant, you may need to have a negative pregnancy test before starting this treatment. Use effective birth control to prevent pregnancy while you are using this medicine and for at least 30 days after your last dose.
  • If you are a man, use condoms when having sex with a woman who is able to get pregnant, even if you have had a vasectomy. Keep using condoms for at least 30 days after your last dose.
  • Tell your doctor right away if a pregnancy occurs while either the mother or the father is using glasdegib.

This medicine may affect fertility (the ability to have children) in men. However, it is important to use birth control to prevent pregnancy because glasdegib can harm an unborn baby. Do not breastfeed while using this medicine, and for at least 30 days after your last dose.

References

  1. https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_210656.pdf
  2. https://www.fda.gov/drugs/fda-approves-glasdegib-aml-adults-age-75-or-older-or-who-have-comorbidities
  3. https://pubchem.ncbi.nlm.nih.gov/compound/Glasdegib
  4. https://pubchem.ncbi.nlm.nih.gov/compound/Glasdegib-maleate
  5. https://medlineplus.gov/druginfo/drug_Da.html
  6. https://www.drugs.com/mtm/glasdegib.html
  7. https://www.mayoclinic.org/drugs-supplements/glasdegib-oral-route/side-effects/drg-20452330?p=1
  8. https://go.drugbank.com/drugs/DB11978
  9. https://en.wikipedia.org/wiki/Glasdegib
  10. https://www.webmd.com/drugs/2/drug-176560/glasdegib-oral/details/list-sideeffects
  11. CompTox Chemicals Dashboard Chemical Lists
  12. 1-((2R,4R)-2-(1H-benzo[d]iMidazol-2-yl)-1-Methylpiperidin-4-yl)-3-(4-cyanophenyl)urea
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  13. NCI Thesaurus Tree
  14. Guide to Pharmacology Target Classification
  15. PubChem
  16. Anatomical Therapeutic Chemical (ATC) classification
    Target-based classification of drugs
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