DAURISMO 100 MG FILM-COATED TABLETS - summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1 NAME OF THE MEDICINAL PRODUCT

Daurismo 100 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient with known effect

Each film-coated tablet contains 5.0 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet (tablet).

11 mm round, pale orange film-coated tablet debossed with “Pfizer” on one side and “GLS 100” on the other side.

4 CLINICAL PARTICULARS

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 and monitoring of laboratory and QT abnormalities

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))________­________________________­________

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

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

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

*

Grading according to CTCAE 4.0: Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.

t 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

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

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).

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 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 (25.0%), abdominal pain (25.0%), rash (25.0%), dyspnoea (25.0%), 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)

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents, ATC code: L01XX63

Mechanism of action

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 for maintaining a leukaemic stem cell (LSC) population thus, glasdegib binding to and inhibiting SMO reduces GLI1 levels in AML cells and the leukaemic initiating potential of AML cells. Hh pathway signalling is also implicated in resistance to chemotherapy and targeted therapy. In a preclinical model of AML, glasdegib in combination with low-dose cytarabine inhibited increases in tumour size to a greater extent than glasdegib or low-dose cytarabine alone. However, mechanism of action of the combination is not fully understood.

Cardiac electrophysiology

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- and open-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 interval change was 8.03 msec (90% CI: 5.85, 10.22 msec). At approximately twice the therapeutic concentration (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 QTc change from baseline of 13.87 msec. None of the subjects met categorical criterion of absolute corrected QT interval of > 480 msec or increase from baseline in corrected QT interval > 30 msec after receiving any treatment. None of the ECG abnormalities were considered clinically significant or reported as adverse events by the investigator (see section 4.4).

Additionally, serial, triplicate ECGs were collected following a single and multiple dosing to evaluate the 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 change from baseline in QTc was 5.30 msec (95% CI: 4.40, 6.24 msec) at the mean observed Cmax at steady state following administration at the recommended 100 mg once daily dose of glasdegib.

Clinical efficacy and safety

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 with previously untreated de novo or secondary AML who were not eligible to receive intensive chemotherapy as defined by meeting at least one of the following criteria: a) age > 75 years, b) severe cardiac disease, c) baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2, or d) baseline serum creatinine > 1.3 mg/dL. Patients were randomised 2:1 to receive Daurismo (100 mg orally once daily) with low-dose cytarabine (20 mg SC twice daily on days 1 to 10 of the 28-day cycle) (n=78) or low-dose cytarabine alone (n=38) in 28-day cycles until disease progression or unacceptable 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 arms were generally balanced with respect to the baseline demographics and disease characteristics. Across both arms, 40% of the AML patients had poor cytogenetic risk and 60% had good/intermediate cytogenetic risk.

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

cytarabine arm.

Table 8. AML efficacy results from Study 1

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 model stratified 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 as absolute neutrophil count > 1000/pl, platelet count > 100,000/pl, < 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 cytarabine alone arm (2.6% [95% CI: 0.0%, 7.7%]).

Paediatric population

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 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Following a single 100 mg dose of glasdegib, peak concentration in plasma is rapidly reached with the median 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.

Food effect

After oral administration of glasdegib tablets, the mean absolute bioavailability is 77.1% compared to intravenous administration. Administration of glasdegib with a high-fat, high-calorie meal resulted in 16% lower exposure (AUCinf) compared to overnight fasting. The impact of food on the pharmacokinetics of glasdegib is not considered clinically relevant. Glasdegib may be administered with 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.

Distribution

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

Biotransformation

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

In vitro interaction studies

In vitro CYP inhibition and induction

In vitro studies indicated that glasdegib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 at clinically relevant concentrations. In vitro studies indicated that glasdegib is not an inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.

In vitro studies of UGT inhibition

In vitro studies indicated that glasdegib is not an inhibitor of uridinediphosphate glucuronosyltran­sferase (UGT)1A4, UGT1A6, UGT2B7, and UGT2B15 at clinically relevant concentrations. Glasdegib may have the potential to inhibit UGT1A1, and possibly UGT1A9, however, clinically relevant drug-drug interactions are not expected.

In vitro studies of organic anion and cation transporter inhibition

In vitro studies indicated that glasdegib is not an inhibitor of organic anion transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, at clinically relevant concentrations.

Elimination

The mean (□ SD) plasma half-life of glasdegib was 17.4 □ 3.7 hours after a single dose of 100 mg glasdegib 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, mean 48.9% and 41.7% of the radioactivity dosed was recovered in urine and faeces, respectively. The overall mean mass balance of the dosed radioactivity in the excreta was 90.6%. Unchanged glasdegib was 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.

Linearity/non-linearity

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

Special populations

Hepatic impairment

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 with moderate hepatic impairment (Child-Pugh Class B), whilst geometric mean AUCinf and Cmax values were 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 hepatic impairment, relative to subjects with normal hepatic function. These changes are not considered to be clinically relevant.

Renal impairment

Data from a dedicated pharmacokinetic trial in subjects with varying degrees of renal function impairment indicate that total glasdegib exposure (AUCinf) increased by 105%, and 102 % with moderate (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 glasdegib exposure (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 be clinically relevant.

Elderly

In patients assigned to treatment with Daurismo with low-dose cytarabine (n=88; Study 1), 97.7% of the patients were aged 65 or older and 60.2% of the patients were aged 75 or older. Study 1 did not include a sufficient number of patients younger than age 65 to determine differences in adverse reactions 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 analyses in adult patients (n=269) indicate that there are no clinically relevant effects of age, gender, race, body weight on the pharmacokinetics of glasdegib.

5.3 Preclinical safety data

The primary target organ findings following repeat oral administration of glasdegib in rats and dogs for up to 26 and 39 weeks in duration, respectively, included the kidney (degeneration/ne­crosis) in rat and dog, the liver (necrosis/inflam­mation) in dog only, and the testis (degeneration), growing incisor teeth (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 muscle tremors/twitching, known class effects of SMO inhibitors, were observed in both species. These systemic toxicities were generally dose-dependent and observed at exposures ranging from approximately < 0.03 to 8-times the clinically relevant exposure based on nonclinical to clinical comparison 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 (axonal degeneration), seminiferous tubule (testicular degeneration), and the clinical observations of muscle tremors/twitching was demonstrated following up to 16-week recovery, whereas partial recovery was demonstrated 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 in telemetered dogs at unbound Cmax exposures approximately 4-times the observed unbound Cmax exposure 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 not clastogenic in the in vitro chromosome aberration assay in human lymphocytes. Glasdegib was not clastogenic 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 included adverse testicular changes with glasdegib at doses □ 50 mg/kg/day, and consisted of minimal to severe hypospermatogenesis characterised by partial to complete loss of spermatogonia, spermatocytes and spermatids and testicular degeneration. Hypospermatogenesis did not recover whereas testicular degeneration did recover. The dose at which adverse testicular effects were observed in male rats was identified as 50 mg/kg/day with corresponding systemic exposures that were approximately 8-times those 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 than clinically relevant.

In embryo-foetal developmental toxicity studies conducted in rats and rabbits, glasdegib was severely toxic to the conceptus as evidenced by complete resorption and/or abortion of foetuses, and teratogenic 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). Severe developmental malformations were observed at maternal systemic exposures lower than the relevant human exposure at the recommended dose of 100 mg once daily.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Sodium starch glycolate

Microcrystalline cellulose (E460(i))

Calcium hydrogen phosphate (anhydrous) (E341ii)

Magnesium stearate (E470b)

Film-coating

Lactose monohydrate

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol (E1521)

Triacetin (E1518)

Iron oxide yellow (E172)

Iron oxide red (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

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

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Pfizer Limited Ramsgate Road Sandwich, Kent CT13 9NJ United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 00057/1688

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/01/2021