Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium
Daurismo 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.
Daurismo should only be prescribed by or under the supervision of a physician experienced in the use of anticancer medicinal products.
The recommended dose is 100 mg glasdegib once daily in combination with low-dose cytarabine (see section 5.1). 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, 3 and 4.
No starting dose adjustments are required on the basis of patient age, race, gender, or body weight (see section 5.2).
Complete blood counts, electrolytes, renal, and hepatic function should be assessed prior to the initiation of Daurismo 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 Daurismo and as indicated clinically thereafter (e.g., if muscle signs and symptoms are reported). Electrocardiograms (ECGs) should be monitored prior to the initiation of Daurismo, 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 (see section 4.4). 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 (see section 4.5). 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 (see section 4.5). Interrupt Daurismo. Resume Daurismo 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 Daurismo to 100 mg daily if an alternative aetiology for the QT prolongation can be identified. |
| Corrected QT interval prolongation and life-threatening arrhythmia | Discontinue Daurismo 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 Daurismo 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 Daurismo and monitor CK levels weekly until resolution to baseline. Monitor muscle symptoms for changes until resolution to baseline. Upon resolution, resume Daurismo 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 Daurismo until resolution to baseline. Re-introduce Daurismo at 50 mg daily and follow the same monitoring recommendations. If symptoms persist, consider discontinuing Daurismo. |
| 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 Daurismo 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 Daurismo at 50 mg daily. CK levels should be measured weekly for 2 months after re-administration of Daurismo and monthly thereafter. |
| Grade 2, 3 or 4 with renal impairment (serum Cr > ULN per CTCAE 4.0) | If renal function is impaired, interrupt Daurismo 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 Daurismo 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 Daurismo and low-dose cytarabine permanently. |
| Neutrophil count less than 0.5 × 109 /L for more than 42 days in the absence of disease | Discontinue Daurismo and low-dose cytarabine permanently. |
Table 4. Dose modification and management for adverse reactions – Nonhaematologic toxicity:
| Adverse reaction: Nonhaematologic toxicity | Dose modification and management recommendations |
|---|---|
| If adverse reaction is attributed to low-dose cytarabine and not to Daurismo, low-dose cytarabine may be modified while Daurismo dosing should be continued. | |
| Grade 3* | Interrupt Daurismo and/or low-dose cytarabine until symptoms improve to Grade ≤1 or return to baseline. Resume Daurismo 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 15 mg or 10 mg. If toxicity recurs, discontinue Daurismo and/or low-dose cytarabine†. |
| Grade 4* | Withhold Daurismo until symptoms improve to Grade ≤1 or return to baseline. Upon recovery, resume Daurismo at a dose of 50 mg or discontinue treatment at the discretion of the prescriber. |
* Grading according to CTCAE 4.0: Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.
† If a decision is made to permanently discontinue low-dose cytarabine, Daurismo should also be discontinued, unless the individual patient is deriving clinical benefit and is tolerating treatment with Daurismo. Abbreviations: CTCAE=Common Terminology Criteria for Adverse Events.
Concomitant use of Daurismo with moderate CYP3A4 inducers should be avoided. If concomitant use of moderate CYP3A4 inducers cannot be avoided, the dose of Daurismo should be increased as tolerated as shown in Table 5. After the moderate CYP3A4 inducer has been discontinued for 7 days, the Daurismo dose taken prior to initiating the moderate CYP3A4 inducer should be resumed (see section 4.5).
Table 5. Dose modification recommendations for Daurismo with concomitant use of moderate CYP3A4 inducers:
| Current dose | Adjusted dose |
|---|---|
| 100 mg orally once daily | 200 mg orally once daily |
| 50 mg orally once daily | 100 mg orally once daily |
No dose adjustments are recommended in patients with mild, moderate, or severe hepatic impairment (see section 5.2).
No dose adjustments are recommended for patients with mild, moderate, or severe renal impairment. No data are available in patients requiring haemodialysis (see section 5.2).
No dose adjustment in elderly patients is required (see section 5.2).
The safety and efficacy of Daurismo in the paediatric population (<18 years of age) have not been established. Daurismo should not be used in the paediatric population because there is no expected significant therapeutic benefit over existing treatments for paediatric patients (see section 5.1).
Daurismo is for oral use. It may be taken with or without food.
Patients should be encouraged to take their dose at approximately the same time each day.
There is no specific antidote for Daurismo. Management of Daurismo overdose should consist of symptomatic treatment and ECG monitoring.
Glasdegib has been administered in clinical studies up to a dose of 640 mg/day. The dose-limiting toxicitiesreported were nausea, vomiting, dehydration, hypotension, fatigue, dizziness, hypoxia, pleural effusion and peripheral oedema.
2 years.
This medicinal product does not require any special storage conditions.
PVC (polyvinyl chloride) blister sealed with aluminium foil containing 10 film-coated tablets, or high-density polyethylene (HDPE) bottle with polypropylene closure containing 30 or 60 film-coated tablets.
Daurismo 25 mg film-coated tablets:
One carton contains 60 film-coated tablets in 6 blisters.
One carton contains 60 film-coated tablets in an HDPE bottle.
Daurismo 100 mg film-coated tablets:
One carton contains 30 film-coated tablets in 3 blisters.
One carton contains 30 film-coated tablets in an HDPE bottle.
Not all pack sizes may be marketed.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
