glasdegib

Absorption: 77% absorbed following oral administration; absorption ↓ by high-fat, high-calorie foods.

Distribution: Extensively distributed to tissues.

Protein Binding: 91%.

Metabolism/Excretion: Mostly metabolized in the liver by the CYP3A4 isoenzyme, and to some extent by CYP2C8 and UGT1A9. 42% excreted in urine (20% as unchanged drug), 42% excreted in feces (20% as unchanged drug).

Half-Life: 17.4 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	1.3–1.8 hr	24 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Blood donation should be avoided during and for ≥30 days following treatment;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Congenital long QT syndrome, HF, electrolyte abnormalities, or concurrent use of QT interval prolonging medications;
Severe renal impairment;
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children.

Adv. Reactions/Side Effects ⬆ ⬇

CV: atrial fibrillation, bradycardia, chest pain, peripheral edema, tachycardia, QT interval prolongation, VENTRICULAR ARRHYTHMIAS

Derm: rash, alopecia

F and E: hyperkalemia, hypokalemia, hypomagnesemia, hyponatremia

GI: abdominal pain, constipation, diarrhea, hyperbilirubinemia, ↑liver enzymes, metallic taste, mucositis, nausea, vomiting

GU: renal impairment, ↓fertility (males)

Hemat: anemia, bleeding, neutropenia, thrombocytopenia

Metab: ↓appetite, ↓weight

MS: ↑creatine kinase (CK), muscle spasm, pain

Neuro: dizziness, fatigue, headache

Resp: cough, dyspnea, pneumonia

Misc: fever

Interactions ⬆ ⬇

Drug-drug:

QT interval prolonging drugs may ↑ risk of QT interval prolongation and torsades de pointes; avoid concurrent use.
Strong CYP3A inhibitors, including ketoconazole, may ↑ levels and risk of toxicity; avoid concurrent use.
Strong CYP3A inducers, including rifampin, and moderate CYP3A inducers, including efavirenz, may ↓ levels and effectiveness; avoid concurrent use; if concurrent use with moderate CYP3A inducer unavoidable, ↓ glasdegib dosage.

Route/Dosage ⬆ ⬇

PO (Adults ): 100 mg once daily on Day 1–28 of each 28-day cycle. Continue treatment for ≥6 cycles (in absence of unacceptable toxicity). Concurrent use of CYP3A inducer: If current dosage 100 mg once daily, ↑ to 200 mg once daily; if current dosage 50 mg once daily, ↑ to 100 mg once daily.

Availability ⬆ ⬇

Tablets: 25 mg; 100 mg

Assessment ⬆ ⬇

Monitor for musculoskeletal adverse reactions (muscle spasms, musculoskeletal pain, myalgia) during therapy.
Monitor ECG prior to starting therapy, 1 wk after starting, and then monthly for next 2 mo to assess for QTc interval prolongation. Repeat ECG if abnormal. If QTc interval >480 msec to 500 msec, assess electrolyte levels and supplement as needed. Adjust concomitant medications with known QTc interval-prolonging effects. Monitor ECG at least weekly for 2 wk following resolution of QTc interval prolongation to ≤480 ms. If QTc interval >500 msec, assess electrolyte levels and supplement as needed. Adjust concomitant medications with known QTc interval-prolonging effect. Hold glasdegib. Resume at 50 mg daily when QTc interval returns to within 30 msec of baseline or ≤480 msec. Monitor ECG at least weekly for 2 wk following resolution of QTc interval prolongation. Consider re-escalating the dose of glasdegib to 100 mg daily if an alternative etiology for QTc interval prolongation is identified. If QTc interval prolongation with life-threatening arrhythmia occurs, permanently discontinue glasdegib.
For other nonhematologic toxicities: Grade 3: Interrupt therapy until symptoms become mild or return to baseline. Resume glasdegib at same dose or at reduced dose of 50 mg once daily. If toxicity recurs, discontinue glasdegib. Grade 4: Discontinue glasdegib permanently.

Lab Test Considerations:

Obtain a negative pregnancy test from females of reproductive potential within 7 days before starting therapy.
- Obtain serum CK and as clinically indicated if muscle symptoms are reported. Obtain serum CK and serum creatinine levels at least weekly in patients with musculoskeletal adverse reactions with concurrent serum CK ↑ >2.5 times upper limit of normal (ULN) until resolution of clinical signs and symptoms. Grade 3 or serum CK elevation 2.5–10 times ULN: Interrupt therapy. Resume glasdegib at same dose level or at reduced dose of 50 mg once daily upon resolution of clinical signs and symptoms. If toxicity recurs, discontinue glasdegib. Grade 4 or serum CK elevation >10 times ULN: Discontinue glasdegib.
- Assess CBC and hepatic function before starting therapy and at least weekly for 1st mo. Manage any abnormalities promptly. If platelets <10 mm³/L for >42 days in the absence of disease, discontinue glasdegib and low-dose cytarabine permanently. If neutrophil count <0.5 mm³/L for >42 days in the absence of disease, permanently discontinue glasdegib and low-dose cytarabine.
- Monitor electrolytes and renal function before starting therapy and monthly for duration of therapy.

Implementation ⬆ ⬇

Administer concurrently with cytarabine on days 1–10 of each 28-day cycle.
PO: Administer once daily, at same time each day, without regard to food. Swallow tablets whole; DNC: Do not crush, break, or chew.

Patient/Family Teaching ⬆ ⬇

Instruct patient to take glasdegib as directed. If vomiting occurs after dose, omit and take next scheduled dose next day. Take missed doses as soon as remembered and at least 12 hr before next scheduled dose; do not take 2 doses within 12 hr. Advise patient to read Medication Guide before starting therapy and with each Rx refill in case of changes.
Advise patient to contact their health care professional immediately if signs and symptoms of QT prolongation (feeling faint, light-headed, or dizzy or feeling heart beating irregularly or fast) occur.
Advise patient not to donate blood or blood products while taking glasdegib and for at least 30 days after the last dose because their blood or blood products might be given to a female of reproductive potential.
Advise males not to donate semen during glasdegib therapy and for at least 30 days after the last dose.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to avoid concurrent use of Rx, OTC, and herbal products without consulting health care professional.
Rep: May cause fetal harm. Advise female of reproductive potential to use effective contraception and to avoid breastfeeding during and for at least 30 days after last dose. Advise males with a female partner of reproductive potential to use effective contraception, including a condom, even after vasectomy, during and for at least 30 days after last dose. May impair male fertility.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇