DAURISMO 100mg tablets medication leaflet

Daurismo 25 mg film-coated tablets

Daurismo 100 mg film-coated tablets

Daurismo 25 mg film-coated tablets

Each film-coated tablet contains glasdegib maleate equivalent to 25 mg of glasdegib.

Each film-coated tablet contains 1.3 mg of lactose monohydrate.

Daurismo 100 mg film-coated tablets

Each film-coated tablet contains glasdegib maleate equivalent to 100 mg of glasdegib.

Each film-coated tablet contains 5 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Daurismo 25 mg film-coated tablets7 mm round, yellow film-coated tablet debossed with “Pfizer” on one side and “GLS 25” on the otherside.

Daurismo 100 mg film-coated tablets11 mm round, pale orange film-coated tablet debossed with “Pfizer” on one side and “GLS 100” onthe other side.

Daurismo is indicated, in combination with low-dose cytarabine, for the treatment of newly diagnosedde novo or secondary acute myeloid leukaemia (AML) in adult patients who are not candidates forstandard induction chemotherapy.

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

The recommended dose is 100 mg glasdegib once daily in combination with low-dose cytarabine (seesection 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 nextscheduled dose is due. If a dose is missed or not taken at the usual time, then it should be taken as soonas the patient remembers unless more than 10 hours have passed since the scheduled dosing time, inwhich case the patient should not take the missed dose. Patients should not take 2 doses at the sametime to make up for a missed dose.

Dose modifications may be required based on individual safety and tolerability. If dose reduction isnecessary, 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 (seesection 5.2).

Assessment of laboratory values and QT abnormalities prior treatment initiation

Complete blood counts, electrolytes, renal, and hepatic function should be assessed prior to theinitiation of treatment and at least once weekly for the first month (see section 4.4). Serum creatininekinase (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) shouldbe monitored prior to the initiation of treatment, approximately one week after initiation, and thenonce 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: Dose modification and management recommendations

ECG QT

Prolonged

Corrected QT Assess electrolyte levels and supplement as clinically indicated.interval 480 msec to500 msec Review and adjust concomitant medicinal products with known QTprolonging effects (see section 4.5).

Monitor ECGs at least weekly for 2 weeks following resolution of QTprolongation to less than or equal to 480 msec.

Corrected QT Assess electrolyte levels and supplement as clinically indicated.interval greater than500 msec Review and adjust concomitant medicinal products with known QTprolonging 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 to480 msec.

Monitor ECGs at least weekly for 2 weeks following resolution of QTprolongation.

Consider re-escalating the dose of Daurismo to 100 mg daily if analternative aetiology for the QT prolongation can be identified.

Corrected QT Discontinue Daurismo permanently.intervalprolongation andlife-threateningarrhythmia

Table 2. Dose modification and management for CK elevations and muscle-related adverseevents

Adverse reaction: Dose modification and management recommendations

Severity of CKelevation

Grade 1 Continue Daurismo at the same dose and monitor CK levels weekly until[CK elevation > resolution to baseline and then monthly. Monitor muscle symptoms for

ULN - 2.5 x ULN] changes until resolution to baseline.

Check renal function (serum creatinine) regularly and ensure that patient isadequately hydrated.

Grade 2 without Interrupt Daurismo and monitor CK levels weekly until resolution torenal impairment baseline.(serum Cr ≤ ULN)[CK elevation > 2.5 Monitor muscle symptoms for changes until resolution to baseline. Uponx ULN - 5 x ULN] resolution, resume Daurismo at the same dose level and measure CKmonthly thereafter.

Check renal function (serum creatinine) regularly and ensure that patient isadequately hydrated.

If symptoms re-occur, interrupt Daurismo until resolution to baseline.

Re-introduce Daurismo at 50 mg daily and follow the same monitoringrecommendations. If symptoms persist, consider discontinuing Daurismo.

Grade 3 or 4 Interrupt Daurismo and monitor CK levels weekly until resolution towithout renal baseline. Monitor muscle symptoms for changes until resolution to baseline.impairment(serum Cr ≤ ULN) Check renal function (serum creatinine) regularly and ensure that patient is[Grade 3 (CK adequately hydrated.elevation > 5 x

ULN - 10 x ULN)] If renal function is not impaired and CK resolves to baseline, consider[Grade 4 (CK resuming Daurismo at 50 mg daily. CK levels should be measured weeklyelevation > 10 x for 2 months after re-administration of Daurismo and monthly thereafter.

ULN)]

Grade 2, 3 or 4 If renal function is impaired, interrupt Daurismo and ensure that the patientwith renal is adequately hydrated and evaluate other secondary causes of renalimpairment impairment.(serum Cr > ULNper CTCAE 4.0) 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 andmonthly 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: Dose modification and management recommendations

Haematologictoxicity

Platelets less than Discontinue Daurismo and low-dose cytarabine permanently.10 x 109/L for morethan 42 days in theabsence of disease

Neutrophil count Discontinue Daurismo and low-dose cytarabine permanently.less than0.5 x 109/L formore than 42 daysin the absence ofdisease

Table 4. Dose modification and management for adverse reactions - Nonhaematologic toxicity

Adverse reaction: Dose modification and management recommendations

Nonhaematologictoxicity If adverse reaction is attributed to low-dose cytarabine and not to Daurismo,low-dose cytarabine may be modified while Daurismo dosing should becontinued.

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 of15 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 tobaseline.

Upon recovery, resume Daurismo at a dose of 50 mg or discontinue treatmentat 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 theindividual 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 useof moderate CYP3A4 inducers cannot be avoided, the dose of Daurismo should be increased astolerated 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 (seesection 4.5).

Table 5. Dose modification recommendations for Daurismo with concomitant use of moderate

Current dose Adjusted dose100 mg orally once daily 200 mg orally once daily50 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).

Elderly (≥ 65 years of age)

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 beenestablished. Daurismo should not be used in the paediatric population because there is no expectedsignificant 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.

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

Embryo-foetal toxicity

Based on its mechanism of action and findings from animal embryo-foetal developmental toxicitystudies, Daurismo can cause embryo-foetal death or severe birth defects when administered to apregnant woman. Pregnant women should be advised of the potential risk to the foetus (see section4.6).

Daurismo should not be used during pregnancy and in women of childbearing potential not usingcontraception. The pregnancy status of female patients of childbearing potential should be verifiedprior to initiating treatment with Daurismo. Women of childbearing potential should be advised toalways use effective contraception during treatment with Daurismo and for at least 30 days after thelast dose (see section 4.6).

Males

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

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

Based on non-clinical safety findings, glasdegib has the potential to impair reproductive function inmales. 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 (myelodysplasticsyndrome) 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 cytarabinecompared 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 firstmonth, and then once monthly for the duration of therapy. Electrolyte abnormalities should becorrected.

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 withcongenital long QT syndrome, congestive heart failure, electrolyte abnormalities, or those who aretaking medicinal products with known QT prolonging effects, more frequent ECG monitoring isrecommended. ECG should be repeated if abnormal. Abnormalities should be managed promptly, anddose 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 atleast once weekly for the first month. Thereafter, hepatic function and blood cell counts should bemonitored 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-dosecytarabine 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 adverseevents. They must be instructed to report promptly any unexplained muscle pain, tenderness orweakness occurring during treatment with Daurismo or if symptoms persist after discontinuingtreatment.

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 oncurrent standards of medical practice and following appropriate treatment guidelines is recommended.

Dose modification or management recommendations should be followed (see section 4.2).

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

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

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

Effects of other medicinal products on the pharmacokinetics of glasdegib

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

Substances that may increase glasdegib plasma concentration

Ketoconazole, a strong inhibitor of CYP3A4, dosed at 400 mg once daily for 7 days, increased themean 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 whenadministering 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 isrecommended (see section 4.4).

Gastric pH altering medicinal products

Coadministration of a single 100 mg glasdegib dose under fasted condition with multiple doses of theproton-pump inhibitor (PPI), rabeprazole, resulted in no change in glasdegib plasma exposure (AUCinfratio: 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

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 healthysubjects. 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 decreaseglasdegib plasma concentrations.

Simulations using physiologic-based pharmacokinetic modelling suggested that coadministration ofefavirenz (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 (seesection 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

Medicinal products known to prolong QT interval

Glasdegib may prolong QT interval. Therefore, the concomitant use of glasdegib with other medicinalproducts 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).

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 GItract) mediated transport at clinically relevant concentrations. Therefore, narrow therapeutic indexsubstrates 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 atclinically relevant concentrations.

If Daurismo is used in women of childbearing potential, they should be advised to avoid becomingpregnant. The pregnancy status of female patients of childbearing potential should be verified priorto initiating treatment. If the patient becomes pregnant while taking Daurismo, the patient should beapprised 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 childbearingpotential who are receiving this medicinal product should always use effective contraception duringtreatment with Daurismo and for at least 30 days after the last dose. If a female patient becomespregnant, or suspects a pregnancy, during treatment with Daurismo or during the 30 days after the lastdose, 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 beadvised 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 apregnant partner or a female partner of childbearing potential during treatment with Daurismo and forat least 30 days after the last dose. Male patients must inform their healthcare provider immediately iftheir female partner becomes pregnant during treatment with Daurismo or during the 30 days after thelast dose (see section 4.4).

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

No studies have been conducted in humans to assess the effect of glasdegib on milk production, itspresence in breast milk, or its effects on the breast-fed child. It is unknown whether glasdegib and itsmetabolites are excreted in human milk. Given the potential for serious adverse reactions inbreast-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).

Based on non-clinical safety findings, glasdegib has the potential to impair reproductive function inmales. 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).

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

The overall safety profile of Daurismo is based on data from clinical studies, including Study 1 in84 patients with AML (N=75) and high-risk MDS (N=9). The median exposure to Daurismo acrossthe 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 reportedadverse reactions leading to permanent discontinuation in patients receiving Daurismo werepneumonia (5.9%), febrile neutropenia (3.5%), and nausea (2.3%).

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

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

All grades

System organ class Preferred term Frequency All grades Grade ≥ 3(%) (%)

Infections and Pneumonia Very common 28.5 23.8infestations Sepsis Common 5.9 5.9

Urinary tract Common 5.9 1.1infection

Blood and lymphatic Anaemia Very common 45.2 41.6system disorders Febrile neutropenia Very common 35.7 35.7

Thrombocytopenia Very common 30.9 30.9

Neutropenia Very common 15.4 11.9

Metabolism and Decreased appetite Very common 33.3 3.5nutrition disorders

Nervous system Dysgeusiaa Very common 26.1 0disorders

Cardiac disorders Electrocardiogram Common 8.3 3.5

QT prolongedb

Atrial fibrillation Common 7.1 2.3

Vascular disorders Haemorrhagesc Very common 45.2 11.9

Respiratory, thoracic Dyspnoea Very common 25 7.1and mediastinaldisorders

Gastrointestinal Nausea Very common 35.7 2.3disorders Diarrhoea Very common 28.5 4.7

Constipation Very common 25 1.1

Abdominal paind Very common 25 0

Vomiting Very common 21.4 2.3

Stomatitis Common 4.7 0

Skin and Rashe Very common 25 2.3subcutaneous tissue Alopecia Very common 10.7 0disorders

Musculoskeletal and Muscle spasmsf Very common 30.9 5.9connective tissue Arthralgia Very common 11.9 0disorders

General disorders and Fatigue Very common 30.9 14.2administration site Weight decreased Very common 20.2 2.3conditions Pyrexia Very common 29.7 2.3

Oedema peripheral Very common 26.1 0

Investigations Platelet count Very common 16.6 16.6decreased

White blood cell Very common 15.4 13count decreased

Neutrophil count Very common 13 13decreased

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

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

c. Haemorrhages includes the following preferred terms: petechiae, epistaxis, contusion, haematoma, haemorrhageintracranial, purpura, rectal haemorrhage, anal haemorrhage, ecchymosis, gastrointestinal haemorrhage, gingival bleeding,haematuria, haemorrhage, mouth haemorrhage, cerebral haemorrhage, conjunctival haemorrhage, eye contusion, eyehaemorrhage, 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.

Muscle spasms

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific antidote for Daurismo. Management of Daurismo overdose should consist ofsymptomatic treatment and ECG monitoring.

Glasdegib has been administered in clinical studies up to a dose of 640 mg/day. The dose-limitingtoxicities reported were nausea, vomiting, dehydration, hypotension, fatigue, dizziness, hypoxia,pleural effusion and peripheral oedema.

Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents, ATC code: L01XJ03

Glasdegib is an inhibitor of the Hedgehog (Hh) signal transduction pathway that binds to Smoothened(SMO), a transmembrane protein, leading to decreased Glioma-Associated Oncogene (GLI)transcription factor activity and downstream pathway signalling. Hh pathway signalling is required formaintaining a leukaemic stem cell (LSC) population thus, glasdegib binding to and inhibiting SMOreduces GLI1 levels in AML cells and the leukaemic initiating potential of AML cells. Hh pathwaysignalling is also implicated in resistance to chemotherapy and targeted therapy. In a preclinical modelof AML, glasdegib in combination with low-dose cytarabine inhibited increases in tumour size to agreater extent than glasdegib or low-dose cytarabine alone. However, mechanism of action of thecombination is not fully understood.

Heart rate corrected QT (QTc) interval prolongation has been observed in patients treated with

Daurismo at a supratherapeutic dose of > 270 mg. The effect of glasdegib administration on corrected

QT interval was evaluated in a randomised, single-dose, double-blind, 4-way crossover, placebo- andopen-label moxifloxacin controlled study in 36 healthy subjects. At therapeutic plasma concentrations(achieved with a 150 mg single dose), the largest, placebo and baseline-adjusted corrected QT intervalchange was 8.03 msec (90% CI: 5.85, 10.22 msec). At approximately twice the therapeuticconcentration (supratherapeutic, achieved with a 300 mg single dose), the QTc change was 13.43 msec(95% CI: 11.25, 15.61 msec). Moxifloxacin (400 mg), used as a positive control, showed a mean QTcchange from baseline of 13.87 msec. None of the subjects met categorical criterion of absolutecorrected QT interval of ≥ 480 msec or increase from baseline in corrected QT interval ≥ 30 msec afterreceiving any treatment. None of the ECG abnormalities were considered clinically significant orreported as adverse events by the investigator (see section 4.4).

Additionally, serial, triplicate ECGs were collected following a single and multiple dosing to evaluatethe effect of single agent glasdegib on the corrected QT interval in 70 patients with advanced cancer(5 mg to 640 mg once daily). Based on the exposure-response analysis, the estimated mean changefrom baseline in QTc was 5.30 msec (95% CI: 4.40, 6.24 msec) at the mean observed Cmax at steadystate following administration at the recommended 100 mg once daily dose of glasdegib.

Daurismo in combination with low-dose cytarabine was investigated in a multicentre, randomised,open-label Phase 2 study (Study 1) in a total of 132 patients, which included 116 patients withpreviously untreated de novo or secondary AML who were not eligible to receive intensivechemotherapy as defined by meeting at least one of the following criteria: a) age ≥ 75 years, b) severecardiac disease, c) baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2, ord) baseline serum creatinine > 1.3 mg/dL. Patients were randomised 2:1 to receive Daurismo (100 mgorally once daily) with low-dose cytarabine (20 mg SC twice daily on days 1 to 10 of the 28-daycycle) (n=78) or low-dose cytarabine alone (n=38) in 28-day cycles until disease progression orunacceptable toxicity. Patients were stratified at randomisation by prognostic risk factor(good/intermediate or poor) based on cytogenetics.

The baseline demographic and disease characteristics are shown in Table 7. The two treatment armswere generally balanced with respect to the baseline demographics and disease characteristics. Acrossboth arms, 40% of the AML patients had poor cytogenetic risk and 60% had good/intermediatecytogenetic risk.

Efficacy was established by an improvement in overall survival (OS defined from the date ofrandomisation to death of any cause) in the Daurismo with low-dose cytarabine arm, compared tolow-dose cytarabine alone. After a median follow-up of approximately 20 months with 81% deathsobserved, the Daurismo with low-dose cytarabine arm was superior to low-dose cytarabine alone in

AML patients (Figure 1). The efficacy results are shown in Table 8.

Table 7. Baseline demographic and disease characteristics in patients with AML

Demographic and disease characteristics Daurismo with Low-dose cytarabinelow-dose cytarabine alone(N=78) (N=38)

Demographics

Median (Min, Max) (Years) 77 (64, 92) 76 (58, 83)≥ 75 years N (%) 48 (62) 23 (61)

Sex, N (%)

Male 59 (76) 23 (61)

Female 19 (24) 15 (39)

Race, N (%)

White 75 (96) 38 (100)

Black or African American 1 (1) 0 (0)

Asian 2 (3) 0 (0)

Disease characteristics

Disease history, N (%)

De Novo AML 38 (49) 18 (47)

Secondary AML 40 (51) 20 (53)

Prior hypomethylating agent (decitabine 11 (14) 6 (16)or azacitidine) use, N (%)

ECOG PSa, N (%)0 to 1 36 (46) 20 (53)2 41 (53) 18 (47)

Cytogenetic risk status, N (%)

Good/Intermediate 49 (63) 21 (55)

Poor 29 (37) 17 (45)

Baseline severe cardiac disease, N (%) 52 (67) 20 (53)

Baseline serum creatinine > 1.3 mg/dL, 15 (19) 5 (13)

N (%)

Abbreviations: AML=acute myeloid leukaemia; ECOG PS=Eastern Cooperative Oncology Group Performance Status;

N=number of patients.

a. Baseline ECOG PS was not reported for one patient in the Daurismo with low-dose cytarabine arm.

Table 8. AML efficacy results from Study 1

Endpoint/study population Daurismo with Low-dose cytarabinelow-dose cytarabine alone

OS in AML study population N=78 N=38

Median survival, months (95% CI) 8.3 (4.7, 12.2) 4.3 (1.9, 5.7)

Hazard ratio (95% CI)a 0.463 (0.299, 0.717)p-valueb 0.0002

OS in de novo AML study population N=38 N=18

Median survival, months (95% CI) 6.6 (3.7, 12.4) 4.3 (1.3, 10.7)

Hazard ratio (95% CI)a 0.670 (0.362, 1.239)p-valueb 0.0991

OS in secondary AML study population N=40 N=20

Median survival, months (95% CI) 9.1 (4.4, 16.5) 4.1 (1.5, 6.4)

Hazard ratio (95% CI)a 0.287 (0.151, 0.548)p-valueb < 0.0001

Good/intermediate cytogenetic risk group N=49 N=21

Median survival, months (95% CI) 11.1 (7.1, 14.9) 4.4 (1.8, 8.7)

Hazard ratio (95% CI)a 0.417 (0.233, 0.744)p-valueb 0.0011

Poor cytogenetic risk group N=29 N=17

Median survival, months (95% CI) 4.4 (3.4, 9.1) 3.1 (1.1, 6.4)

Hazard ratio (95% CI)a 0.528 (0.273, 1.022)

Endpoint/study population Daurismo with Low-dose cytarabinelow-dose cytarabine alonep-valueb 0.0269

Abbreviations: AML=acute myeloid leukaemia; CI=confidence interval; N=number of patients; OS=overall survival.

a. Hazard ratio (Daurismo with low-dose cytarabine/low-dose cytarabine alone) based on the Cox Proportional hazards modelstratified by prognosis stratum.

b. 1-sided p-value from stratified log-rank test based on cytogenetic risk.

Figure 1. Kaplan-Meier plot of overall survival for AML patients

Abbreviations: CI=confidence interval; LDAC=low-dose cytarabine; OS=overall survival.

Improvement in OS was consistent across pre-specified subgroups by cytogenetic risk.

Based on investigator reported response, a numerically higher complete response (CR) rate (defined asabsolute neutrophil count ≥ 1 000/μl, platelet count ≥ 100 000/μl, < 5% bone marrow blasts,transfusion independent, and no extramedullary disease) was achieved for AML patients in the

Daurismo with low-dose cytarabine arm (17.9% [95% CI: 9.4%, 26.5%]) vs the low-dose cytarabinealone arm (2.6% [95% CI: 0.0%, 7.7%]).

The European Medicines Agency has waived the obligation to submit the results of studies with

Daurismo in all subsets of the paediatric population in treatment of AML (see section 4.2 forinformation on paediatric use).

Following a single 100 mg dose of glasdegib, peak concentration in plasma is rapidly reached with themedian Tmax of 2 hours. Following repeat 100 mg once daily dosing to steady state, glasdegib median

Tmax ranged from approximately 1.3 hours to 1.8 hours.

After oral administration of glasdegib tablets, the mean absolute bioavailability is 77.1% compared tointravenous administration. Administration of glasdegib with a high-fat, high-calorie meal resulted in16% lower exposure (AUCinf) compared to overnight fasting. The impact of food on thepharmacokinetics of glasdegib is not considered clinically relevant. Glasdegib may be administeredwith or without food.

Following 100 mg once daily glasdegib dosing, the mean (coefficient of variation, %CV) of glasdegib

Cmax was 1 252 ng/mL (44%) and AUCtau was 17 210 ng*hr/mL (54%) in patients with cancer.

Glasdegib is 91% bound to human plasma proteins in vitro. The mean (%CV) apparent volume ofdistribution (Vz/F) was 188 (20) L following a single dose of 100 mg glasdegib in patients withhaematologic malignancies.

The primary metabolic pathways for glasdegib were comprised of N-demethylation, glucuronidation,oxidation, and dehydrogenation. In plasma, the N-desmethyl and N-glucuronide metabolites ofglasdegib accounted for 7.9% and 7.2% of the circulating radioactivity, respectively. Othermetabolites in plasma individually accounted for < 5% of circulating radioactivity.

In vitro interaction studies

In vitro CYP3A4 inhibition and induction

In vitro studies indicated that glasdegib is affected by inhibitors and inducers of CYP3A4. Please seesection 4.5 for further discussion of moderate CYP3A4 inducers. A strong inhibitor of CYP3A4increased 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. A strong inducer of

CYP3A4, reduced the mean AUCinf by 70% and Cmax by 35% of a single 100 mg dose of glasdegib inhealthy subjects. Use of glasdegib with strong inducers should be avoided; caution should be use whenadministering concomitantly glasdegib with strong CYP3A4 inhibitors (see section 4.5).

The mean ( SD) plasma half-life of glasdegib was 17.4  3.7 hours after a single dose of 100 mgglasdegib in patients. The geometric mean oral clearance after multiple dosing was 6.45 L/hr.

Following oral administration of a 100 mg radiolabeled dose of glasdegib to healthy subjects, mean48.9% and 41.7% of the radioactivity dosed was recovered in urine and faeces, respectively. Theoverall mean mass balance of the dosed radioactivity in the excreta was 90.6%. Unchanged glasdegibwas the major component of human plasma, accounting for 69.4% of the total drug-related material.

Unchanged glasdegib recovered in the urine and faeces accounted for 17.2% and 19.5% of the dose,respectively.

The steady state systemic glasdegib exposure (Cmax and AUCtau) increased in a dose-proportionalmanner over the dosing range of 5 mg to 600 mg once daily.

Data from a dedicated pharmacokinetic trial have shown that plasma exposures for total glasdegib(AUCinf and Cmax) were similar between subjects with normal hepatic function and subjects withmoderate hepatic impairment (Child-Pugh Class B), whilst geometric mean AUCinf and Cmax valueswere 24% and 42% lower, respectively, for subjects with severe hepatic impairment (Child-Pugh

Class C), compared to the normal hepatic function group. The glasdegib unbound exposure (unbound

AUCinf) is increased by 18% and 16% in subjects with moderate and severe impairment, respectively,relative to subjects with normal hepatic function. Peak glasdegib unbound exposure (unbound Cmax)increased by 1%, for moderate hepatic impairment and decreased by 11% for severe hepaticimpairment, relative to subjects with normal hepatic function. These changes are not considered to beclinically relevant.

Data from a dedicated pharmacokinetic trial in subjects with varying degrees of renal functionimpairment indicate that total glasdegib exposure (AUCinf) increased by 105%, and 102% withmoderate (30 mL/min ≤ eGFR < 60 mL/min), and severe (eGFR < 30 mL/min) renal impairment,respectively, relative to subjects with normal (eGFR ≥ 90 mL/min) renal function. Peak glasdegibexposure (Cmax) increased by 37%, and 20% for subjects with moderate, and severe renal impairment,respectively, relative to subjects with normal renal function. These changes are not considered to beclinically relevant.

In patients assigned to treatment with Daurismo with low-dose cytarabine (n=88; Study 1), 97.7% ofthe patients were aged 65 or older and 60.2% of the patients were aged 75 or older. Study 1 did notinclude a sufficient number of patients younger than age 65 to determine differences in adversereactions reported from patients older than 65.

Age, race, gender, and body weight

There are limited data in patients younger than 65 years of age. Population pharmacokinetic analysesin adult patients (n=269) indicate that there are no clinically relevant effects of age, gender, race, bodyweight on the pharmacokinetics of glasdegib.

The primary target organ findings following repeat oral administration of glasdegib in rats and dogsfor up to 26 and 39 weeks in duration, respectively, included the kidney (degeneration/necrosis) in ratand dog, the liver (necrosis/inflammation) in dog only, and the testis (degeneration), growing incisorteeth (necrosis/broken), growing bone (partial to full closure of epiphysis), and peripheral nerve(axonal degeneration) in rat only. Additional clinical observations of alopecia, weight loss, and muscletremors/twitching, known class effects of SMO inhibitors, were observed in both species. Thesesystemic toxicities were generally dose-dependent and observed at exposures ranging fromapproximately < 0.03 to 8-times the clinically relevant exposure based on non-clinical to clinicalcomparison of the observed unbound AUC at the recommended clinical dose of 100 mg once daily.

Complete reversibility of toxicities to the kidney (degeneration/necrosis), peripheral nerve (axonaldegeneration), seminiferous tubule (testicular degeneration), and the clinical observations of muscletremors/twitching was demonstrated following up to 16-week recovery, whereas partial recovery wasdemonstrated in the liver (necrosis/inflammation). The observation of alopecia, bone and teeth effects,and testicular hypospermatogenesis did not recover. In addition, QTc prolongation was identified intelemetered dogs at unbound Cmax exposures approximately 4-times the observed unbound Cmaxexposure at the recommended clinical dose of 100 mg once daily.

Glasdegib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and was notclastogenic in the in vitro chromosome aberration assay in human lymphocytes. Glasdegib was notclastogenic or aneugenic in the rat micronucleus assay.

Carcinogenicity studies have not been conducted with glasdegib.

In repeat-dose toxicity studies in rats, findings observed in the male reproductive tract includedadverse testicular changes with glasdegib at doses  50 mg/kg/day, and consisted of minimal to severehypospermatogenesis characterised by partial to complete loss of spermatogonia, spermatocytes andspermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testiculardegeneration did recover. The dose at which adverse testicular effects were observed in male rats wasidentified as 50 mg/kg/day with corresponding systemic exposures that were approximately 8-timesthose associated with the observed human exposure at the 100 mg once daily dose (based on unbound

AUC in respective species). Safety margin for NOAEL (10 mg/kg/day) is 0.6, hence lower thanclinically relevant.

In embryo-foetal developmental toxicity studies conducted in rats and rabbits, glasdegib was severelytoxic to the conceptus as evidenced by complete resorption and/or abortion of foetuses, andteratogenic effects at lower dose levels. Teratogenic effects included craniofacial malformations,malformed limbs, paws/digits, trunk and tail, dilation of brain, malpositioned/malformed eyes,misshapen head, small tongue, absent palate, teeth and viscera, diaphragmatic hernia, oedema,persistent truncus arteriosus, heart defects, absent lung, absent trachea, rib and vertebral abnormalities,and malformed or absent structures in the appendicular skeleton (notably the long bones). Severedevelopmental malformations were observed at maternal systemic exposures lower than the relevanthuman exposure at the recommended dose of 100 mg once daily.

Sodium starch glycolate

Microcrystalline cellulose (E460(i))

Calcium hydrogen phosphate (anhydrous) (E341ii)

Magnesium stearate (E470b)

Lactose monohydrate

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol (E1521)

Triacetin (E1518)

Iron oxide yellow (E172)

Iron oxide red (E172) (100 mg tablets only)

Not applicable.

4 years.

This medicinal product does not require any special storage conditions.

PVC (polyvinyl chloride) blister sealed with aluminium foil containing 10 film-coated tablets, orhigh-density polyethylene (HDPE) bottle with polypropylene closure containing 30 or 60 film-coatedtablets.

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 localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

Daurismo 25 mg film-coated tablets

EU/1/20/1451/001

EU/1/20/1451/002

Daurismo 100 mg film-coated tablets

EU/1/20/1451/003

EU/1/20/1451/004

Date of first authorisation: 26 June 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.