Glasdegib

Glasdegib is an inhibitor of the Hedgehog (Hh) signal transduction pathway. Hh signalling is needed to maintain the leukaemic stem cell population in acute myeloid leukaemia (AML) and is also implicated in resistance to chemotherapy and targeted therapy. Glasdegib is given together with low-dose cytarabine.

Mechanism of Action

• Target: glasdegib binds to Smoothened (SMO), a transmembrane protein. This decreases the activity of the Glioma-Associated Oncogene (GLI) transcription factors and downstream pathway signalling.
• Effect on leukaemic cells: inhibiting SMO reduces GLI1 levels in AML cells and lowers their leukaemia-initiating potential.
• Combination: in a preclinical AML model, glasdegib with low-dose cytarabine limited tumour growth more than either medicine alone. The mechanism of the combination is not fully understood.
• Cardiac electrophysiology: QTc prolongation has been seen at a supratherapeutic dose above 270 mg. In a crossover study in 36 healthy subjects, the largest placebo- and baseline-adjusted QTc change was 8.03 msec at therapeutic concentrations (a single 150 mg dose) and 13.43 msec at about twice those concentrations (a single 300 mg dose). No subject reached an absolute QTc of 480 msec or more, or a rise of 30 msec or more from baseline.

Pharmacokinetics

• Absorption: rapid; after a single 100 mg dose the median time to peak concentration is 2 hours (about 1.3 to 1.8 hours at steady state). Absolute oral bioavailability is 77.1% compared with intravenous dosing. A high-fat, high-calorie meal lowers exposure (AUC) by 16%, which is not clinically relevant. At 100 mg once daily in patients with cancer, the mean peak concentration was 1,252 ng/mL.
• Distribution: 91% bound to human plasma proteins in vitro; apparent volume of distribution about 188 L after a single 100 mg dose in patients with haematological malignancies.
• Metabolism: the main pathways are N-demethylation, glucuronidation, oxidation and dehydrogenation. CYP3A4 accounts for most of the metabolism in vitro, with minor roles for CYP2C8 and UGT1A9. The N-desmethyl and N-glucuronide metabolites make up 7.9% and 7.2% of circulating radioactivity; no other metabolite exceeds 5%.
• Elimination: mean plasma half-life 17.4 hours after a single 100 mg dose; geometric mean oral clearance after repeated dosing 6.45 L/h. After a radiolabelled dose, about 49% was recovered in urine and 42% in faeces.
• Special populations: age, race, sex and body weight do not call for a different starting dose. No dose adjustment is recommended in hepatic or renal impairment of any degree.

• Acute myeloid leukaemia (AML): in combination with low-dose cytarabine, for the treatment of newly diagnosed de novo or secondary AML in adults who are not candidates for standard induction chemotherapy.

• Hypersensitivity to glasdegib or to any of the excipients listed in section 6.1 of the SmPC.

The safety data come from a clinical study in 84 patients (75 with AML and 9 with high-risk myelodysplastic syndrome) treated with glasdegib and low-dose cytarabine, with a median exposure of 75.5 days. Reactions seen in 20% or more of patients were anaemia and haemorrhage (45.2% each), febrile neutropenia and nausea (35.7% each), decreased appetite, fatigue, muscle spasms, thrombocytopenia, pyrexia, diarrhoea, pneumonia, dysgeusia, peripheral oedema, constipation, abdominal pain, rash, dyspnoea, vomiting and weight loss. The most frequent reasons for dose reduction were muscle spasms (4.7%), fatigue and febrile neutropenia (3.5% each), and anaemia, thrombocytopenia and ECG QT prolongation (2.3% each); the most frequent reasons for permanent discontinuation were pneumonia (5.9%), febrile neutropenia (3.5%) and nausea (2.3%).

Very common (≥1/10): pneumonia; anaemia, febrile neutropenia, thrombocytopenia, neutropenia; decreased appetite; dysgeusia (including ageusia); haemorrhage (a grouped term covering bleeding at many sites, among them epistaxis, bruising, gastrointestinal, intracranial and conjunctival bleeding); dyspnoea; nausea, diarrhoea, constipation, abdominal pain, vomiting; rash, alopecia; muscle spasms, arthralgia; fatigue, weight decreased, pyrexia, peripheral oedema; decreased platelet, white blood cell and neutrophil counts.

Common (≥1/100 to <1/10): sepsis, urinary tract infection; ECG QT prolonged (a grouped term that includes ventricular tachycardia); atrial fibrillation; stomatitis.

Important serious reactions are febrile neutropenia, pneumonia and sepsis, bleeding (grade 3 or higher in 11.9% of patients), QT prolongation with arrhythmia, and muscle-related events with raised creatine kinase.

Glasdegib is cleared mainly by CYP3A4, so strong modulators of this enzyme change its exposure.

• Strong CYP3A4 inhibitors: ketoconazole (400 mg daily for 7 days) raised the AUC of a single 200 mg glasdegib dose about 2.4-fold and the peak concentration by 40%. Use with caution with strong inhibitors (for example boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, telaprevir, troleandomycin, voriconazole, ritonavir, grapefruit or grapefruit juice); where possible choose a medicine with no or minimal CYP3A4 inhibition.
• Strong CYP3A4 inducers: rifampicin (600 mg daily for 11 days) reduced the AUC of a single 100 mg dose by 70% and the peak concentration by 35%. Avoid strong inducers such as rifampicin, carbamazepine, enzalutamide, mitotane and phenytoin. St John’s wort also induces CYP3A and should be avoided.
• Moderate CYP3A4 inducers: avoid; if the combination cannot be avoided, the glasdegib dose is increased (see Administration and Dosage).
• QT-prolonging medicines: review all co-medication; for medicines with known QT-prolonging effects, alternatives should be considered, and ECG monitoring is more frequent when they are used.
• Acid-reducing medicines: proton-pump inhibitors, H2-receptor antagonists and antacids are permitted. Rabeprazole did not change glasdegib exposure.
• Food: tablets may be taken with or without food, at about the same time each day.

Glasdegib is prescribed by, or under the supervision of, a physician experienced in the use of anticancer medicinal products. The tablet is taken by mouth once daily, with or without food, at about the same time each day.

Recommended Dose

• 100 mg once daily in combination with low-dose cytarabine, continued for as long as the patient derives clinical benefit.
• If a reduction is needed for safety or tolerability, the dose is 50 mg once daily.

Monitoring Before and During Treatment

• Before starting: complete blood count, electrolytes, renal and hepatic function, serum creatine kinase (CK) and an ECG. Pregnancy status of women of childbearing potential is verified (see Special Instructions).
• At least once weekly for the first month: blood counts, electrolytes, renal and hepatic function. Afterwards electrolytes and renal function are checked monthly, and blood counts and hepatic function as clinically indicated but at least monthly.
• ECG about one week after starting, then monthly for the next two months; more often in congenital long QT syndrome, congestive heart failure, electrolyte abnormalities or when taking QT-prolonging medicines.
• CK as clinically indicated, for example when muscle symptoms are reported.

Dose Adjustments for Side Effects

• QT prolongation (confirmed on at least 2 separate ECGs): for a corrected QT of 480 to 500 msec, correct electrolytes, review QT-prolonging medicines and check ECGs at least weekly for 2 weeks after the QT returns to 480 msec or less. Above 500 msec, also interrupt glasdegib and resume at 50 mg once daily when the QT is within 30 msec of baseline or 480 msec or less; consider returning to 100 mg if another cause is found. With life-threatening arrhythmia, stop permanently.
• CK elevation and muscle events: grade 1 (up to 2.5 times the upper limit of normal) continue and monitor CK weekly. Grade 2 without renal impairment: interrupt, resume at the same dose once CK is back to baseline, and restart at 50 mg once daily if symptoms return. Grade 3 or 4 without renal impairment: interrupt, and consider resuming at 50 mg once daily if renal function is normal and CK has returned to baseline. Grade 2 to 4 with renal impairment: interrupt, hydrate, look for other causes, and consider 50 mg once daily only if CK and creatinine return to baseline; otherwise stop permanently.
• Haematological toxicity: platelets below 10 × 10⁹/L, or neutrophils below 0.5 × 10⁹/L, for more than 42 days in the absence of disease: stop glasdegib and low-dose cytarabine permanently.
• Non-haematological toxicity: grade 3, interrupt until grade 1 or baseline, then resume at the same dose or 50 mg (cytarabine at the same dose or reduced to 15 mg or 10 mg); stop if it recurs. Grade 4, withhold until grade 1 or baseline, then resume at 50 mg or stop at the prescriber’s discretion. A reaction attributed to cytarabine alone can be handled by changing cytarabine while glasdegib continues. If low-dose cytarabine is stopped permanently, glasdegib is stopped too unless the patient is benefiting and tolerating it.
• Moderate CYP3A4 inducers: if unavoidable, increase 100 mg to 200 mg once daily, or 50 mg to 100 mg once daily, as tolerated; return to the previous dose 7 days after the inducer is stopped.

Special Populations

• Elderly (65 years and over): no dose adjustment.
• Renal impairment: no adjustment for mild, moderate or severe impairment; no data in patients on haemodialysis.
• Hepatic impairment: no adjustment for mild, moderate or severe impairment.
• Children and adolescents: safety and efficacy under 18 years have not been established, and glasdegib should not be used because no significant benefit over existing treatments is expected.

Missed or Vomited Dose

• A vomited dose is not replaced; wait for the next scheduled dose.
• A missed dose is taken as soon as remembered unless more than 10 hours have passed since the scheduled time; then it is skipped. Never take two doses at the same time.

Pregnancy Check, Contraception and Condoms

• Risk to the unborn child: from its mechanism of action and animal studies, glasdegib can cause embryo-foetal death or severe birth defects. It must not be used during pregnancy, or in women of childbearing potential who are not using contraception.
• Pregnancy ruled out before starting: the pregnancy status of women of childbearing potential must be verified before treatment begins.
• Women: use effective contraception throughout treatment and for at least 30 days after the last dose. A pregnancy or suspected pregnancy during treatment, or within those 30 days, must be reported to the healthcare provider immediately.
• Men: glasdegib may be present in semen. Male patients with female partners must always use effective contraception, including a condom (with spermicide, if available), even after a vasectomy, during treatment and for at least 30 days after the last dose, to avoid exposing a pregnant partner or a partner who could become pregnant. They must not donate semen during this time and must tell their healthcare provider at once if their partner becomes pregnant.

QT Interval Prolongation

In the randomised study, grade 3 or 4 QT prolongation on ECG occurred in 3.5% of patients on glasdegib with low-dose cytarabine and 2.4% on low-dose cytarabine alone. Electrolytes are checked before treatment, weekly in the first month and then monthly, and abnormalities are corrected. Concomitant medicines are reviewed, and alternatives are considered for medicines that prolong the QT interval or strongly inhibit CYP3A4.

Blood Counts, Liver and Kidney Function

Blood counts and hepatic function can need dose modification (see Administration and Dosage). Patients with existing renal impairment or risk factors for renal dysfunction are monitored closely; renal function is assessed before starting and weekly in the first month, and electrolytes and renal function are then checked monthly.

Muscle-Related Adverse Events

Muscle spasms occurred in 22.6% of patients on glasdegib with low-dose cytarabine and 4.8% on low-dose cytarabine alone. Every patient is told of this risk and must report any unexplained muscle pain, tenderness or weakness promptly, including symptoms that persist after stopping. Serum CK is measured before starting and as clinically indicated.

Breastfeeding and Fertility

• Breastfeeding: not recommended during treatment and for at least one week after the last dose; it is unknown whether glasdegib passes into breast milk.
• Fertility: glasdegib may impair male reproductive function, and men should seek advice on fertility preservation before treatment. From its mechanism of action it may also impair female fertility.

Excipients

The tablets contain lactose; patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. Each tablet contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

Glasdegib has a minor influence on the ability to drive and use machines. Patients with fatigue or other symptoms such as muscle cramps, pain or nausea should take care.

Daurismo needs no special storage conditions. It is supplied in PVC/aluminium-foil blisters of 10 tablets or in high-density polyethylene bottles with a polypropylene closure: 25 mg cartons hold 60 tablets (6 blisters or 1 bottle) and 100 mg cartons hold 30 tablets (3 blisters or 1 bottle). Not all pack sizes may be marketed.

4 years. Do not use after the expiry date on the pack.

Prescription only (Rx), on restricted medical prescription (Annex II B): prescribed by, or under the supervision of, a physician experienced in anticancer medicines. Daurismo is taken at home, so it is supplied to the patient or to the treating clinic on prescription. The SmPC makes the following part of treatment: pregnancy status verified before treatment starts, effective contraception for women and condoms for men during treatment and for at least 30 days after the last dose. These are conditions of treatment, not a pregnancy-prevention programme with dispensing limits.