Active Ingredient: Glasdegib
Glasdegib is indicated, in combination with low-dose cytarabine, for the treatment of newly diagnosed de novo or secondary acute myeloid leukaemia (AML) in adult patients who are not candidates for standard induction chemotherapy.
For this indication, competent medicine agencies globally authorize below treatments:
Oral
100 - 100 mg
From 100 To 100 mg once every day
The recommended dose is 100 mg glasdegib once daily in combination with low-dose cytarabine. Glasdegib should be continued as long as the patient is deriving clinical benefit.
If a dose is vomited, a replacement dose should not be administered; patients should wait until the next scheduled dose is due. If a dose is missed or not taken at the usual time, then it should be taken as soon as the patient remembers unless more than 10 hours have passed since the scheduled dosing time, in which case the patient should not take the missed dose. Patients should not take 2 doses at the same time to make up for a missed dose.
Dose modifications may be required based on individual safety and tolerability. If dose reduction is necessary, then the dose of glasdegib should be reduced to 50 mg taken orally once daily.
Dose modification and management guidelines for specific adverse reactions are provided in Tables 1, 2 and 3.
No starting dose adjustments are required on the basis of patient age, race, gender, or body weight.
Complete blood counts, electrolytes, renal, and hepatic function should be assessed prior to the initiation of glasdegib and at least once weekly for the first month. Electrolytes and renal function should be monitored once monthly for the duration of therapy. Serum creatine kinase (CK) levels should be obtained prior to initiating glasdegib and as indicated clinically thereafter (e.g., if muscle signs and symptoms are reported). Electrocardiograms (ECGs) should be monitored prior to the initiation of glasdegib, approximately one week after initiation, and then once monthly for the next two months to assess for QT corrected for heart rate (QTc) prolongation. ECG should be repeated if abnormal. Certain patients may require more frequent and ongoing ECG monitoring. Abnormalities should be managed promptly.
Table 1. Dose modification and management for adverse reactions – QT interval prolongation (corrected QT interval prolongation on at least 2 separate electrocardiograms (ECGs)):
| Adverse reaction: ECG QT Prolonged | Dose modification and management recommendations |
|---|---|
| Corrected QT interval 480 msec to 500 msec | Assess electrolyte levels and supplement as clinically indicated. Review and adjust concomitant medicinal products with known QT prolonging effects. Monitor ECGs at least weekly for 2 weeks following resolution of QT prolongation to less than or equal to 480 msec. |
| Corrected QT interval greater than 500 msec | Assess electrolyte levels and supplement as clinically indicated. Review and adjust concomitant medicinal products with known QT prolonging effects. Interrupt glasdegib. Resume glasdegib at a reduced dose of 50 mg once daily when corrected QT interval returns to within 30 msec of baseline or less than or equal to 480 msec. Monitor ECGs at least weekly for 2 weeks following resolution of QT prolongation. Consider re-escalating the dose of glasdegib to 100 mg daily if an alternative aetiology for the QT prolongation can be identified. |
| Corrected QT interval prolongation and life-threatening arrhythmia | Discontinue glasdegib permanently. |
Table 2. Dose modification and management for CK elevations and muscle-related adverse events:
| Adverse reaction: Severity of CK elevation | Dose modification and management recommendations |
|---|---|
| Grade 1 [CK elevation >ULN – 2.5 x ULN] | Continue glasdegib at the same dose and monitor CK levels weekly until resolution to baseline and then monthly. Monitor muscle symptoms for changes until resolution to baseline. Check renal function (serum creatinine) regularly and ensure that patient is adequately hydrated. |
| Grade 2 without renal impairment (serum Cr ≤ ULN) [CK elevation >2.5 x ULN – 5 x ULN] | Interrupt glasdegib and monitor CK levels weekly until resolution to baseline. Monitor muscle symptoms for changes until resolution to baseline. Upon resolution, resume glasdegib at the same dose level and measure CK monthly thereafter. Check renal function (serum creatinine) regularly and ensure that patient is adequately hydrated. If symptoms re-occur, interrupt glasdegib until resolution to baseline. Re-introduce glasdegib at 50 mg daily and follow the same monitoring recommendations. If symptoms persist, consider discontinuing glasdegib. |
| Grade 3 or 4 without renal impairment (serum Cr ≤ ULN) [Grade 3 (CK elevation >5 x ULN – 10 x ULN)] [Grade 4 (CK elevation >10 x ULN)] | Interrupt glasdegib and monitor CK levels weekly until resolution to baseline. Monitor muscle symptoms for changes until resolution to baseline. Check renal function (serum creatinine) regularly and ensure that patient is adequately hydrated. If renal function is not impaired and CK resolves to baseline, consider resuming glasdegib at 50 mg daily. CK levels should be measured weekly for 2 months after re-administration of glasdegib and monthly thereafter. |
| Grade 2, 3 or 4 with renal impairment (serum Cr > ULN per CTCAE 4.0) | If renal function is impaired, interrupt glasdegib and ensure that the patient is adequately hydrated and evaluate other secondary causes of renal impairment. Monitor CK and serum creatinine levels weekly until resolution to baseline. Monitor muscle symptoms for changes until resolution to baseline. If CK and serum creatinine levels return to baseline consider resuming glasdegib at 50 mg daily and measure CK levels weekly for 2 months and monthly thereafter; otherwise discontinue treatment permanently. |
Abbreviations: CK=creatine kinase; Cr=creatinine; ULN=upper limit of normal; CTCAE=Common Terminology Criteria for Adverse Events.
Table 3. Dose modification and management for adverse reactions – Haematologic toxicity:
| Adverse reaction: Haematologic toxicity | Dose modification and management recommendations |
|---|---|
| Platelets less than 10 × 109 /L for more than 42 days in the absence of disease | Discontinue glasdegib and low-dose cytarabine permanently. |
| Neutrophil count less than 0.5 × 109 /L for more than 42 days in the absence of disease | Discontinue glasdegib and low-dose cytarabine permanently. |
It may be taken with or without food.
Patients should be encouraged to take their dose at approximately the same time each day.
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