4.1. Therapeutic indications

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.

4.2. Posology and method of administration

Daurismo should only be prescribed by or under the supervision of a physician experienced in the use of anticancer medicinal products.

Posology

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.

Delayed or missed doses of glasdegib

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

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).

Assessment of laboratory values and QT abnormalities prior to treatment initiation

Complete blood counts, electrolytes, renal, and hepatic function should be assessed prior to the initiation of treatment and at least once weekly for the first month (see section 4.4). Serum creatinine kinase (CK) levels should be obtained prior to initiating therapy and as indicated clinically thereafter (e.g. if muscle signs and symptoms are reported; see section 4.4). Electrocardiograms (ECGs) should be monitored prior to the initiation of treatment, approximately one week after initiation, and then once monthly for the next two months to assess for QT corrected for heart rate (QTc) prolongation (see section 4.4).

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 x 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 x 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.

Dose modification for concomitant use with moderate CYP3A4 inducers

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

Special populations

Hepatic impairment

No dose adjustments are recommended in patients with mild, moderate, or severe hepatic impairment (see section 5.2).

Renal impairment

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).

Elderly (≥ 65 years of age)

No dose adjustment in elderly patients is required (see section 5.2).

Paediatric population

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).

Method of administration

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.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Embryo-foetal toxicity

Based on its mechanism of action and findings from animal embryo-foetal developmental toxicity studies, Daurismo can cause embryo-foetal death or severe birth defects when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the foetus (see section 4.6).

Daurismo should not be used during pregnancy and in women of childbearing potential not using contraception. The pregnancy status of female patients of childbearing potential should be verified prior to initiating treatment with Daurismo. Women of childbearing potential should be advised to always use effective contraception during treatment with Daurismo and for at least 30 days after the last dose (see section 4.6).

Males

Glasdegib may be present in semen. Male patients with female partners should be advised of the potential risk of exposure through semen and to always use effective contraception, including a condom (with spermicide, if available), even after vasectomy, to avoid exposure of a pregnant partner or a female partner of childbearing potential during treatment with Daurismo and for at least 30 days after the last dose (see section 4.6).

If a female patient or female partner of a male patient becomes pregnant, or suspects a pregnancy during treatment with Daurismo or during the 30 days after the last dose, they must inform their healthcare provider immediately (see section 4.6).

Based on non-clinical safety findings, glasdegib has the potential to impair reproductive function in males. Men should seek advice on effective fertility preservation prior to initiating treatment with Daurismo (see section 4.6).

QT interval prolongation

In a randomised study (Study 1) of patients with AML and high-risk MDS (myelodysplastic syndrome) treated with Daurismo with low-dose cytarabine vs low-dose cytarabine alone, Grade 3/4 ECG QT prolonged was reported in 3.5% of patients treated with Daurismo with low-dose cytarabine compared to 2.4% of the patients treated with low-dose cytarabine alone.

Electrolytes should be assessed prior to initiation of Daurismo, at least once weekly for the first month, and then once monthly for the duration of therapy. Electrolyte abnormalities should be corrected.

Concomitant medicinal products should be assessed. For medicinal products that have known QT prolonging effects and/or strong CYP3A4 inhibitor potential, alternatives should be considered.

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 QTc prolongation. In patients with congenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medicinal products with known QT prolonging effects, more frequent ECG monitoring is recommended. ECG should be repeated if abnormal. Abnormalities should be managed promptly, and dose modifications should be considered (see sections 4.2 and 4.5).

Blood cell counts and hepatic function monitoring

Complete blood counts and hepatic function should be assessed prior to the initiation of therapy and at least once weekly for the first month. Thereafter, hepatic function and blood cell counts should be monitored as clinically indicated but at least monthly. In the event of hepatic or haematologic toxicity, dose modifications may be needed (see section 4.2).

Muscle-related adverse events

In Study 1, muscle spasms were observed in 22.6% of patients treated with Daurismo with low-dose cytarabine compared to 4.8% of the patients treated with low-dose cytarabine alone.

All patients starting therapy with Daurismo must be informed of the risk of muscle-related adverse events. They must be instructed to report promptly any unexplained muscle pain, tenderness or weakness occurring during treatment with Daurismo or if symptoms persist after discontinuing treatment.

Serum CK levels should be obtained prior to initiating Daurismo and as clinically indicated thereafter (e.g. if muscle signs and symptoms are reported). Management of high-grade CK elevation based on current standards of medical practice and following appropriate treatment guidelines is recommended. Dose modification or management recommendations should be followed (see section 4.2).

Renal impairment

Patients with pre-existing renal impairment or risk factors for renal dysfunction should be monitored closely. Renal function should be assessed prior to initiation of therapy and at least once weekly for the first month of therapy with Daurismo. Electrolytes and renal function should be monitored once monthly for the duration of therapy (see section 4.2).

Excipients

Lactose intolerance

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose‑galactose malabsorption should not take this medicinal product.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on the pharmacokinetics of glasdegib

In vitro, CYP3A4 is responsible for the majority of glasdegib depletion and contributed to the formation of other minor oxidative metabolites, with CYP2C8 and UGT1A9 playing a minor role in the metabolism of glasdegib.

Substances that may increase glasdegib plasma concentration

CYP3A4 inhibitors

Ketoconazole, a strong inhibitor of CYP3A4, dosed at 400 mg once daily for 7 days, increased the mean area under the curve (AUCinf) by ~2.4-fold and maximum plasma concentration (Cmax) by 40% of a single 200 mg oral dose of glasdegib in healthy subjects. Caution should be used when administering concomitantly with strong CYP3A4 inhibitors (e.g. boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, telaprevir, troleandomycin, voriconazole, ritonavir, grapefruit or grapefruit juice) as an increase in glasdegib plasma concentration may occur. If possible, alternate concomitant medicinal product with no or minimal CYP3A4 inhibition potential is recommended (see section 4.4).

Gastric pH altering medicinal products

Coadministration of a single 100 mg glasdegib dose under fasted condition with multiple doses of the proton-pump inhibitor (PPI), rabeprazole, resulted in no change in glasdegib plasma exposure (AUCinf ratio: 100.6%). Concomitant administration of glasdegib with acid-reducing agents (including PPIs, H2-receptor antagonists, and locally acting antacids) is permitted.

Substances that may decrease glasdegib plasma concentration

CYP3A4 inducers

Rifampicin, a strong inducer of CYP3A4, administered at a dose of 600 mg once daily for 11 days, reduced the mean AUCinf by 70% and Cmax by 35% of a single 100 mg dose of glasdegib in healthy subjects. Concomitant use with strong CYP3A4 inducers (e.g. rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin and St. John's Wort) should be avoided, as this is likely to decrease glasdegib plasma concentrations.

Simulations using physiologic-based pharmacokinetic modelling suggested that coadministration of efavirenz (a moderate inducer of CYP3A4) with glasdegib decreased glasdegib AUCinf by 55% and Cmax by 25%. Concomitant use of moderate CYP3A4 inducers (e.g. bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided as they may also reduce glasdegib plasma concentrations (see section 4.4). If concomitant use of moderate CYP3A4 inducers cannot be avoided, the dose of Daurismo should be increased (see section 4.2).

Effect of glasdegib on the pharmacokinetics of other medicinal products

Pharmacodynamic interactions

Medicinal products known to prolong QT interval

Glasdegib may prolong QT interval. Therefore, the concomitant use of glasdegib with other medicinal products known to prolong QT interval or induce Torsades de Pointes (such as amiodarone, disopyramide, dofetilide, ibutilide, sotalol, quinidine, droperidol, haloperidol, methadone, moxifloxacin, pimozide) should be carefully considered (see sections 4.2 and 4.4).

Pharmacokinetic interactions

Drug transporters

In vitro studies indicated that glasdegib may have the potential to inhibit P-glycoprotein (P-gp, gastrointestinal [GI] tract) and breast cancer resistance protein (BCRP, systemically and at the GI tract) mediated transport at clinically relevant concentrations. Therefore, narrow therapeutic index substrates of P-gp (e.g. digoxin) or BCRP should be used with caution in combination with glasdegib.

In vitro studies of transporter inhibition

In vitro studies indicated that glasdegib may have the potential to inhibit (MATE)1 and MATE2K at clinically relevant concentrations.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

If Daurismo is used in women of childbearing potential, they should be advised to avoid becoming pregnant. The pregnancy status of female patients of childbearing potential should be verified prior to initiating treatment. If the patient becomes pregnant while taking Daurismo, the patient should be apprised of the potential hazard to the foetus.

Based on its mechanism of action and findings from animal embryo-foetal developmental studies, Daurismo can cause foetal harm when administered to a pregnant woman. Women of childbearing potential who are receiving this medicinal product should always use effective contraception during treatment with Daurismo and for at least 30 days after the last dose. If a female patient becomes pregnant, or suspects a pregnancy, during treatment with Daurismo or during the 30 days after the last dose, she must notify her healthcare provider immediately (see section 4.4).

Males

Glasdegib may be present in semen. Male patients should not donate semen during treatment with Daurismo and for at least 30 days after the last dose. Male patients with female partners should be advised of the potential risk of exposure through semen and to always use effective contraception, including a condom (with spermicide, if available), even after a vasectomy, to avoid exposure of a pregnant partner or a female partner of childbearing potential during treatment with Daurismo and for at least 30 days after the last dose. Male patients must inform their healthcare provider immediately if their female partner becomes pregnant during treatment with Daurismo or during the 30 days after the last dose (see section 4.4).

Pregnancy

There are no data on the use of Daurismo in pregnant women. Based on its mechanism of action and findings in animal embryo-foetal developmental toxicity studies, glasdegib can cause foetal harm when administered to a pregnant woman (see section 5.3). Daurismo should not be used during pregnancy and in women of childbearing potential not using contraception (see section 4.4).

Breast-feeding

No studies have been conducted in humans to assess the effect of glasdegib on milk production, its presence in breast milk, or its effects on the breast-fed child. It is unknown whether glasdegib and its metabolites are excreted in human milk. Given the potential for serious adverse reactions in breast‑feeding children from glasdegib, breast-feeding is not recommended during treatment with Daurismo and for at least one week after the last dose (see section 5.3).

Fertility

Based on non-clinical safety findings, glasdegib has the potential to impair reproductive function in males. Men should seek advice on effective fertility preservation prior to initiating treatment with Daurismo. Based on its mechanism of action, Daurismo may impair female fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

Daurismo has minor influence on the ability to drive and use machines. However, patients experiencing fatigue or other symptoms (e.g. muscle cramps, pain, nausea) affecting the ability to react normally while taking Daurismo should exercise caution when driving or operating machines.

4.8. Undesirable effects

Summary of the safety profile

The overall safety profile of Daurismo is based on data from clinical studies, including Study 1 in 84 patients with AML (N=75) and high-risk MDS (N=9). The median exposure to Daurismo across the dataset was 75.5 days.

The most frequently (≥ 20%) reported adverse reactions in patients receiving Daurismo were anaemia (45.2%), haemorrhages (45.2%), febrile neutropenia (35.7%), nausea (35.7%), decreased appetite (33.3%), fatigue (30.9%), muscle spasms (30.9%), thrombocytopenia (30.9%), pyrexia (29.7%), diarrhoea (28.5%), pneumonia (28.5%), dysgeusia (26.1%), oedema peripheral (26.1%), constipation (25%), abdominal pain (25%), rash (25%), dyspnoea (25%), vomiting (21.4%), and weight decreased (20.2%).

The most frequently reported adverse reactions leading to dose reductions in patients receiving Daurismo were muscle spasms (4.7%), fatigue (3.5%), febrile neutropenia (3.5%), anaemia (2.3%), thrombocytopenia (2.3%), and electrocardiogram QT prolonged (2.3%). The most frequently reported adverse reactions leading to permanent discontinuation in patients receiving Daurismo were pneumonia (5.9%), febrile neutropenia (3.5%), and nausea (2.3%).

Tabulated list of adverse reactions

Table 6 presents adverse reactions reported with Daurismo. The adverse reactions are listed by system organ class and frequency category. Frequency categories are defined as: very common (≥ 1/10) and common (≥ 1/100 to < 1/10). Within each frequency grouping, adverse reactions are presented in decreasing order of all grade frequencies.

Table 6: Adverse reactions reported in clinical studies (N=84)

System organ class

Preferred term

All grades

Frequency

All grades (%)

Grade ≥ 3 (%)

Infections and infestations

Pneumonia

Sepsis

Urinary tract infection

Very common

Common

Common

28.5

5.9

5.9

23.8

5.9

1.1

Blood and lymphatic system disorders

Anaemia

Febrile neutropenia

Thrombocytopenia

Neutropenia

Very common

Very common

Very common

Very common

45.2

35.7

30.9

15.4

41.6

35.7

30.9

11.9

Metabolism and nutrition disorders

Decreased appetite

Very common

33.3

3.5

Nervous system disorders

Dysgeusiaa

Very common

26.1

0

Cardiac disorders

Electrocardiogram QT prolongedb

Atrial fibrillation

Common

Common

8.3

7.1

3.5

2.3

Vascular disorders

Haemorrhagesc

Very common

45.2

11.9

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Very common

25

7.1

Gastrointestinal disorders

Nausea

Diarrhoea

Constipation

Abdominal paind

Vomiting

Stomatitis

Very common

Very common

Very common

Very common

Very common

Common

35.7

28.5

25

25

21.4

4.7

2.3

4.7

1.1

0

2.3

0

Skin and subcutaneous tissue disorders

Rashe

Alopecia

Very common

Very common

25

10.7

2.3

0

Musculoskeletal and connective tissue disorders

Muscle spasmsf

Arthralgia

Very common

Very common

30.9

11.9

5.9

0

General disorders and administration site conditions

Fatigue

Weight decreased

Pyrexia

Oedema peripheral

Very common

Very common

Very common

Very common

30.9

20.2

29.7

26.1

14.2

2.3

2.3

0

Investigations

Platelet count decreased

White blood cell count decreased

Neutrophil count decreased

Very common

Very common

Very common

16.6

15.4

13

16.6

13

13

a. Dysgeusia includes the following preferred terms: dysgeusia, ageusia.

b. Electrocardiogram QT prolonged includes the following preferred terms: electrocardiogram QT prolonged, ventricular tachycardia.

c. Haemorrhages includes the following preferred terms: petechiae, epistaxis, contusion, haematoma, haemorrhage intracranial, purpura, rectal haemorrhage, anal haemorrhage, ecchymosis, gastrointestinal haemorrhage, gingival bleeding, haematuria, haemorrhage, mouth haemorrhage, cerebral haemorrhage, conjunctival haemorrhage, eye contusion, eye haemorrhage, gastric haemorrhage, haematemesis, haemoptysis, haemorrhoidal haemorrhage, implant site haematoma, injection site bruising, retroperitoneal haematoma, subarachnoid haemorrhage, thrombotic thrombocytopenic purpura, tracheal haemorrhage, urethral haemorrhage.

d. Abdominal pain includes the following preferred terms: abdominal pain, abdominal pain upper, abdominal pain lower.

e. Rash includes the following preferred terms: erythema, pruritus, rash, rash macular, rash maculo-papular, rash pruritic.

f. Muscle spasms includes the following preferred terms: muscle contractions involuntary, muscle spasms, muscle tightness, musculoskeletal pain, myalgia.

Description of selected adverse reactions

Muscle spasms

In Study 1, muscle spasms (all grades) were reported in 22.6% of patients in the Daurismo with low‑dose cytarabine arm compared to 4.8% in the low-dose cytarabine alone arm. Grades 3 and 4 muscle spasms were reported in 4.7% of patients in the Daurismo with low-dose cytarabine arm compared to none in the low-dose cytarabine alone arm.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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 toxicities reported were nausea, vomiting, dehydration, hypotension, fatigue, dizziness, hypoxia, pleural effusion and peripheral oedema.