Ksospata
UkraineTable of Contents
I N S T R U C T I O N for medical use of the medicinal product XOSPATA® (XOSPATA®)
Composition:
Active substance: gilteritinib;
1 film-coated tablet contains 40 mg of gilteritinib (as fumarate);
Excipients: mannitol (E 421), hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate; film coating: hypromellose, talc, macrogol, titanium dioxide, yellow iron oxide (E172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical characteristics: round, light-yellow film-coated tablets, embossed with the company's logo and the number "235" on one side of the tablet.
Pharmacotherapeutic group. Antineoplastic agents, protein kinase inhibitors.
ATC code L01E X13.
Pharmacological Properties.
Pharmacodynamics.
Mechanism of Action
Gilteritinib fumarate is an inhibitor of FLT3 and AXL.
Gilteritinib suppresses FLT3 receptor signaling and proliferation in cells with exogenous expression of FLT3, including FLT3-ITD, FLT3-D835Y, and FLT3-ITD-D835Y, subsequently inducing apoptosis in leukemic cells expressing FLT3-ITD.
Pharmacodynamic Effects
In patients with relapsed or refractory acute myeloid leukemia (AML) receiving gilteritinib at a dose of 120 mg, substantial (> 90%) inhibition of FLT3 phosphorylation was observed, which was rapid (within 24 hours after the first dose) and sustained; these characteristics were confirmed by ex vivo plasma inhibitory activity (PIA) quantitative analysis.
QT Interval Prolongation
Concentration-dependent QTcF prolongation relative to baseline was observed at gilteritinib doses ranging from 20 to 450 mg. The predicted mean change from baseline in QTcF at the mean steady-state Cmax (282.0 ng/mL) with a daily dose of 120 mg was 4.96 ms (upper one-sided 95% CI = 6.20 ms).
Clinical Efficacy and Safety
Relapsed or Refractory AML
Efficacy and safety were evaluated in a clinical trial (Phase 3) with active control (2215-CL-0301).
Clinical Trial ADMIRAL (2215-CL-0301)
ADMIRAL was an open-label, multicenter, randomized clinical trial (Phase 3) involving adult patients with relapsed or refractory AML with FLT3 mutation, confirmed using the LeukoStrat® CDx FLT3 Mutation Assay. In this study, 371 patients were randomized in a 2:1 ratio to receive either gilteritinib or one of the following types of salvage chemotherapy (247 patients in the gilteritinib group and 124 in the salvage chemotherapy group):
∙ Cytarabine 20 mg twice daily via subcutaneous (SC) injection or intravenous (IV) infusion for 10 days (days 1–10) (LoDAC);
∙ Azacitidine 75 mg/m² once daily subcutaneously or intravenously for 7 days (days 1–7);
∙ Mitoxantrone 8 mg/m², etoposide 100 mg/m², and cytarabine 1000 mg/m² once daily intravenously for 5 days (days 1–5) (MEC);
∙ Granulocyte colony-stimulating factor 300 µg/m² once daily subcutaneously for 5 days (days 1–5), fludarabine 30 mg/m² once daily intravenously for 5 days (days 2–6), cytarabine 2000 mg/m² once daily intravenously for 5 days (days 2–6), and idarubicin 10 mg/m² once daily intravenously for 3 days (days 2–4) (FLAG-Ida).
Patients enrolled in the trial had relapsed or confirmed refractory disease after first-line AML therapy and were stratified by response to prior AML treatment and prior choice of chemotherapy—either high or low intensity. Although the study included patients with various cytogenetic abnormalities associated with AML, patients with acute promyelocytic leukemia (APL) or therapy-related AML were excluded.
Sixteen patients were randomized but did not receive treatment in the study (1 patient in the gilteritinib group and 15 patients in the chemotherapy group). Gilteritinib was administered orally at an initial dose of 120 mg daily until unacceptable toxicity or lack of clinical benefit occurred. Dose reductions were permitted to manage (reduce manifestations of) adverse reactions, and dose escalation was allowed for patients who did not respond to the initial 120 mg dose.
Among patients randomized to receive salvage chemotherapy, 60.5% were assigned to the high-intensity therapy subgroup and 39.5% to the low-intensity subgroup. MEC and FLAG-Ida treatment courses were administered for up to two cycles, depending on response after the first cycle. LoDAC and azacitidine therapies were administered in continuous 4-week cycles until unacceptable toxicity or lack of clinical benefit occurred.
Demographic and baseline characteristics were well balanced between the two treatment groups. The median age at randomization was 62 years (range 20–84 years) in the gilteritinib group and 62 years (range 19–85 years) in the salvage chemotherapy group. In the study, 42% of patients were aged 65 years or older, and 12% were aged 75 years or older. Fifty-four percent of patients were female. The majority of patients in the study were of White race (59.3%); 27.5% were of Asian race, 5.7% were Black, 4% were of other races, and race was unknown in 3.5%. The majority of patients (83.8%) had an ECOG performance status of 0 or 1. Patients had confirmed mutations as follows: FLT3-ITD only (88.4%), FLT3-TKD only (8.4%), or both FLT3-ITD and FLT3-TKD (1.9%). Twelve percent of patients had received prior treatment with another FLT3 inhibitor. The majority of patients had AML with intermediate-risk cytogenetics (73%), 10% had adverse-risk, 1.3% had favorable-risk, and 15.6% had unclassified cytogenetic data.
Prior to gilteritinib treatment, 39.4% of patients had confirmed diagnosis of primary refractory AML, with most of these patients classified as refractory after one cycle of induction chemotherapy; 19.7% experienced AML relapse after allogeneic hematopoietic stem cell transplantation (HSCT), and 41% had AML relapse without prior allogeneic HSCT.
The primary efficacy endpoint for the final analysis was overall survival (OS) in the intent-to-treat (ITT) population; it was measured from the date of randomization to death from any cause (number of events analyzed: 261). Patients randomized to the gilteritinib group had significantly longer overall survival compared to the traditional chemotherapy group (HR 0.637; 95% CI 0.490–0.830; one-sided p-value 0.0004). Median OS was 9.3 months for patients receiving gilteritinib and 5.6 months for those receiving chemotherapy. Efficacy was further supported by rates of complete remission (CR)/complete remission with partial hematologic recovery (CRh) (Table 1).
Table 1
Overall Survival and Complete Remission Rates in the ADMIRAL Clinical Trial in Patients with Relapsed or Refractory AML
| Parameter |
Gilteritinib (N = 247) |
Chemotherapy (N = 124) |
| Overall Survival |
||
| Deaths, n (%) |
171 (69.2) |
90 (72.6) |
| Median, months (95% CI) |
9.3 (7.7, 10.7) |
5.6 (4.7, 7.3) |
| Hazard ratio (95% CI) |
0.637 (0.490, 0.830) |
|
| p-value (one-sided) |
0.0004 |
|
| 1-year survival, % |
37.1 (30.7, 43.6) |
16.7 (9.9, 25) |
| Complete Remission |
||
| CRa (95% CIb) |
21.1% (16.1, 26.7) |
10.5% (5.7, 17.3) |
| CRhс (95% CIb) |
13% (9, 17.8) |
4.8% (1.8, 10.2) |
| CR/CRh (95% CIb) |
34% (28.1, 40.3) |
15.3% (9.5, 22.9) |
CI – confidence interval
a CR status was defined as absolute neutrophil count ≥ 1.0 × 109/L, platelets ≥ 100 × 109/L, normal bone marrow with < 5% blasts, likely red blood cells, no platelet transfusion, and absence of signs of extramedullary leukemia.
b 95% CI were calculated using the exact method based on the binomial distribution.
c CRh status was defined as bone marrow blasts < 5%, partial hematologic recovery, absolute neutrophil count ≥ 0.5 × 109/L and platelets ≥ 50 × 109/L, absence of signs of extramedullary leukemia, and not meeting criteria for CR.
Among patients who achieved CR/CRh, the median time to first response was 3.7 months (range: 0.9 to 10.6 months) in the gilteritinib group and 1.2 months (range: 1 to 2.6 months) in the salvage chemotherapy group. The median time to achieve best response of CR/CRh was 3.8 months (range: 0.9 to 16 months) in the gilteritinib group and 1.2 months (range: 1 to 2.6 months) in the salvage chemotherapy group.
Clinical trial CHRYSALIS (2215-CL-0101)
The supplemental (supportive) clinical trial 2215-CL-0101 dose escalation (phase 1/2) included 157 patients with FLT3-mutated AML who received 1 or more prior lines (cycles) of therapy in the combined dose group (i.e., 80 mg, 120 mg, or 200 mg); 31.2% of patients received 1 prior line of therapy, and 68.8% received more than 1 prior line of therapy.
The observed response rate (CR/CRh) in study 2215-CL-0101 among patients who received more than 1 prior line of therapy was 21.4% and 15.7% for the 120 mg dose and combined dosing, respectively. The median OS was 7.2 months and 7.1 months for the 120 mg dose and combined dosing, respectively.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Xospata in one or more subsets of the paediatric population for the treatment of acute myeloid leukaemia. See section "Paediatric population" for information on paediatric use.
Pharmacokinetics
Absorption
Following oral administration of gilteritinib, peak plasma concentrations were observed at mean tmax values ranging approximately between 4 and 6 hours in healthy volunteers and patients with relapsed or refractory acute myeloid leukaemia (AML). Gilteritinib undergoes first-pass absorption with an estimated absorption rate constant (ka) of 0.43 h-1 and a time delay of 0.34 hours based on population PK modelling. The mean maximum steady-state concentration (Cmax) is 282.0 ng/mL (CV% = 50.8), and the area under the plasma concentration-time curve over a 24-hour dosing interval (AUC0-24) is 6180 ng•h/mL (CV% = 46.4) following once-daily administration of 120 mg gilteritinib. At steady state following once-daily dosing, plasma concentrations are achieved within 15 days with approximately 10-fold accumulation.
Effect of food
In healthy adults, Cmax and AUC of gilteritinib decreased by approximately 26% and less than 10%, respectively, when a single 40 mg dose of gilteritinib was administered with a high-fat meal compared to administration under fasting conditions. The mean tmax was delayed by approximately 2 hours when gilteritinib was administered with a high-fat meal.
Distribution
Population estimates of central and peripheral volumes of distribution were 1092 L and 1100 L, respectively. These data suggest that gilteritinib is widely distributed into tissues beyond plasma, indicating extensive tissue distribution. Plasma protein binding in vivo in humans is approximately 90%, with gilteritinib primarily bound to albumin.
Biotransformation
Based on in vitro studies, gilteritinib is primarily metabolized via the CYP3A4 cytochrome system. Primary metabolites in humans include compounds M17 (formed via N-dealkylation and oxidation), M16 and M10 (both formed via N-dealkylation); these metabolites are also observed in animals. None of these three metabolites exceeded 10% of the total exposure of the parent drug. The pharmacological activity of the metabolites with respect to FLT3 and AXL receptors has not been established.
Drug transporter interactions
In vitro experiments demonstrated that gilteritinib is a substrate of P-gp and BCRP. Gilteritinib may potentially inhibit BCRP, P-gp, and OST1 at clinically relevant concentrations (see section "Interaction with other medicinal products and other forms of interactions").
Elimination
Following a single administration of radiolabelled [14C] gilteritinib, gilteritinib was primarily eliminated in faeces, with 64.5% of the total administered dose quantitatively recovered in faeces. Approximately 16.4% of the total dose was excreted in urine as unchanged drug and metabolites. Gilteritinib plasma concentrations declined bi-exponentially, with a mean calculated population elimination half-life of 113 hours. The calculated apparent clearance (CL/F) based on population PK modelling is 14.85 L/h.
Linearity/non-linearity of dose
Overall, gilteritinib showed linear, dose-proportional pharmacokinetics following single and multiple doses in the range of 20 to 450 mg in patients with relapsed or refractory AML.
Special populations
A population pharmacokinetic analysis was conducted to evaluate the impact of intrinsic and extrinsic covariates on predicted gilteritinib exposure in patients with relapsed or refractory AML. Covariate analysis showed that age (20 to 90 years) and body weight (36 to 157 kg) had statistically significant effects; however, the predicted change in gilteritinib exposure levels was less than 2-fold.
Hepatic impairment
The effect of hepatic impairment on the pharmacokinetics of gilteritinib was studied in subjects with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment. Results indicate that unbound gilteritinib exposure in subjects with mild or moderate hepatic impairment is comparable to that in subjects with normal hepatic function. The impact of mild hepatic impairment [as defined by NCI-ODWG] on gilteritinib exposure was also evaluated using population PK modelling; results showed minimal difference in predicted steady-state gilteritinib exposure compared to typical patients with relapsed or refractory AML and normal hepatic function.
Gilteritinib has not been studied in patients with severe hepatic impairment (Child-Pugh class C).
Renal impairment
The pharmacokinetics of gilteritinib were evaluated in five patients with severe renal impairment (CrCL 15 – < 30 mL/min) and in four patients with end-stage renal disease (CrCL < 15 mL/min). In patients with severe renal impairment or end-stage renal disease, mean Cmax of gilteritinib increased by 1.4-fold and mean AUCinf of gilteritinib increased by 1.5-fold compared to corresponding values in subjects with normal renal function (n = 8) (see sections "Method of administration and dosage" and "Special warnings and precautions for use").
Clinical characteristics.
Indications.
The medicinal product Xospata is indicated as monotherapy for adult patients with relapsed or refractory acute myeloid leukemia (AML) with FLT3 mutation.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients.
Interaction with other medicinal products and other forms of interaction.
Gilteritinib is primarily metabolized by CYP3A enzymes, which may be induced or inhibited by certain concomitant medicinal products.
Effect of other medicinal products on Xospata therapy
Inducers of CYP3A/P-gp
Concomitant use of Xospata with strong CYP3A/P-gp inducers (e.g., phenytoin, rifampicin, and St. John's wort) should be avoided, as they may reduce plasma concentrations of gilteritinib. In healthy subjects receiving a single 20 mg dose of gilteritinib, concomitant administration of rifampicin (600 mg), a strong CYP3A/P-gp inducer, decreased the mean Cmax of gilteritinib by 27% and the mean AUC by 70%, respectively, compared to subjects who received a single dose of gilteritinib alone (see section "Special precautions for use").
Inhibitors of CYP3A, P-gp and/or BCRP
Strong inhibitors of CYP3A, P-gp, and/or BCRP (e.g., voriconazole, itraconazole, posaconazole, clarithromycin, erythromycin, captopril, carvedilol, ritonavir, azithromycin) may increase plasma concentrations of gilteritinib. A single 10 mg dose of gilteritinib administered together with itraconazole (200 mg once daily for 28 days), a strong inhibitor of CYP3A, P-gp, and BCRP, resulted in approximately a 20% increase in mean Cmax and a 2.2-fold increase in mean AUCinf in healthy subjects compared to subjects who received only a single dose of gilteritinib. Exposure to gilteritinib increased by approximately 1.5-fold in patients with relapsed or refractory AML receiving concomitant treatment with a strong CYP3A, P-gp, and/or BCRP inhibitor (see section "Special precautions for use").
Effect of Xospata on other medicinal products
Gilteritinib as an inhibitor or inducer
Gilteritinib is not an inhibitor or inducer of CYP3A4 or an inhibitor of MATE1 in vivo. The pharmacokinetics of midazolam (a sensitive CYP3A4 substrate) were not significantly altered (Cmax and AUC increased by approximately 10%) after 15 days of daily gilteritinib administration (300 mg) in patients with FLT3-mutated relapsed or refractory AML. Furthermore, the pharmacokinetics of cephalexin (a sensitive MATE1 substrate) were not significantly altered (Cmax and AUC decreased by less than 10%) after 15 days of daily gilteritinib administration (200 mg) in patients with FLT3-mutated relapsed or refractory AML.
Gilteritinib is an inhibitor of P-gp, BCRP, and OST1 in vitro. Due to the lack of clinical data, it cannot be excluded that gilteritinib may inhibit these transporters at therapeutic doses. Caution is recommended when co-administering gilteritinib with substrates of P-gp (e.g., digoxin, dabigatran etexilate), BCRP (e.g., mitoxantrone, methotrexate, rosuvastatin), and OST1 (e.g., metformin).
Effect on 5HT2B or non-specific sigma receptors
Based on in vitro data, gilteritinib may reduce the effect of medicinal products targeting the 5HT2B receptor or non-specific sigma receptors (selective serotonin reuptake inhibitors, e.g., escitalopram, fluoxetine, sertraline).
Concomitant use of these medicinal products with Xospata should be avoided unless their use is considered necessary for patient care.
Special precautions for use.
Differentiation syndrome
Gilteritinib has been associated with differentiation syndrome (see section "Adverse reactions").
Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms and clinical manifestations of differentiation syndrome include fever, dyspnea, pleural effusion, pericardial effusion, pulmonary edema, hypotension, rapid weight gain, peripheral edema, rash, and renal dysfunction.
In suspected cases of differentiation syndrome, corticosteroid therapy should be initiated together with hemodynamic monitoring until symptoms resolve.
If severe signs and/or symptoms persist for more than 48 hours after initiation of corticosteroid therapy, administration of KXOSPATA should be discontinued until signs and symptoms are no longer serious (see sections "Dosage and administration" and "Adverse reactions").
Corticosteroids may be tapered after resolution of symptoms, but should be continued for at least 3 additional days. Symptoms of differentiation syndrome may recur if corticosteroid treatment is discontinued prematurely.
Posterior reversible encephalopathy syndrome (PRES)
Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving KXOSPATA (see section "Adverse reactions"). PRES is a rare reversible neurological disorder that may present with rapidly developing symptoms including seizures, headache, confusion, visual and neurological disturbances, with or without hypertension and altered mental status. If PRES is suspected, it should be confirmed by brain imaging, preferably magnetic resonance imaging (MRI). Discontinuation of KXOSPATA is recommended in patients who develop PRES (see sections "Dosage and administration" and "Adverse reactions").
QT interval prolongation
Prolonged ventricular repolarization (QT interval) has occurred during treatment with gilteritinib (see section "Adverse reactions"). QT interval prolongation is observed within the first three months of gilteritinib treatment. Therefore, electrocardiograms (ECG) should be performed prior to starting treatment, on Day 8 and Day 15 of Cycle 1, and prior to the start of each of the next three months of treatment. Caution should be exercised when administering to patients with relevant cardiac history. Hypokalaemia or hypomagnesaemia may increase the risk of QT interval prolongation. Therefore, hypokalaemia and hypomagnesaemia should be corrected prior to and during treatment with KXOSPATA.
Treatment with KXOSPATA should be interrupted in patients with QTcF > 500 msec (see section "Dos游戏副本 and administration").
The decision to reinitiate gilteritinib treatment after confirmed QT interval prolongation should be based on careful consideration of benefits and risks. If KXOSPATA is restarted at a reduced dose, ECG should be performed 15 days after resuming treatment and prior to the start of each of the next three months of treatment. In clinical studies, QTcF > 500 msec occurred in 12 patients. Three patients discontinued and resumed treatment without recurrence of QT interval prolongation.
Pancreatitis
Cases of pancreatitis have been reported. Patients who develop signs and symptoms suggestive of pancreatitis should be evaluated and monitored. Administration of KXOSPATA should be interrupted and resumed at a reduced dose once signs and symptoms of pancreatitis have resolved (see section "Dosage and administration").
Severe renal impairment
Exposure to gilteritinib may be increased in patients with severe renal impairment or end-stage renal disease. Patients should be closely monitored for signs of toxicity during treatment with KXOSPATA (see section "Pharmacological properties").
Interactions
Concomitant administration of CYP3A/P-gp inducers may lead to reduced exposure to gilteritinib and thus to a risk of loss of efficacy. Therefore, concomitant use of gilteritinib with strong CYP3A4/P-gp inducers should be avoided (see section "Interaction with other medicinal products and other forms of interaction").
Caution is required when co-administering gilteritinib with medicinal products that are strong CYP3A, P-gp, and/or breast cancer resistance protein (BCRP) inhibitors (such as voriconazole, itraconazole, posaconazole, and clarithromycin), as they may increase gilteritinib exposure. Alternative medicinal products with less inhibitory effect on CYP3A, P-gp, and/or BCRP should be considered. In situations where no adequate therapeutic alternatives are available, patients should be closely monitored for signs of toxicity during gilteritinib treatment (see section "Interaction with other medicinal products and other forms of interaction").
Gilteritinib may reduce the effect of medicinal products targeting 5HT2B receptors or non-specific sigma receptors. Therefore, concomitant use of gilteritinib with these agents should be avoided unless considered necessary for patient care (see section "Interaction with other medicinal products and other forms of interaction").
Embryo-foetal toxicity and contraception
Pregnant women should be informed of the potential risk to the foetus (see section "Pregnancy or breastfeeding"). Women of reproductive potential should be advised to undergo a pregnancy test within 7 days prior to starting treatment with KXOSPATA and to use effective contraception during treatment and for at least 6 months after treatment ends. Women using hormonal contraceptives should add a barrier method of contraception. Men with female partners of reproductive potential should be advised to use effective contraception during treatment and for at least 4 months after the last dose of KXOSPATA.
Use during pregnancy or breastfeeding.
Women of reproductive potential / Contraception in men and women
Women of reproductive potential are recommended to undergo pregnancy testing within 7 days prior to starting treatment with KXOSPATA and to use effective contraceptive methods (methods with a pregnancy rate of less than 1%) during treatment and for 6 months after treatment. It is unknown whether gilteritinib may reduce the effectiveness of hormonal contraceptives; therefore, women using hormonal contraceptives should add a barrier method of contraception. Men with reproductive potential should be advised to use effective contraception during treatment and for at least 4 months after the last dose of KXOSPATA (see section "Special precautions for use").
Pregnancy
Gilteritinib may cause substantial harm to the foetus when administered to pregnant women. Data on gilteritinib use in pregnant women are lacking or limited. Reproductive studies in rats showed that gilteritinib caused embryo-fetal growth suppression, embryonic and foetal death, and teratogenicity. KXOSPATA is not recommended for use in pregnant women or in women of reproductive potential who are not using effective contraception.
Breastfeeding
It is unknown whether gilteritinib or its metabolites are excreted in human milk. Available animal data show excretion of gilteritinib and its metabolites in milk of lactating rats and distribution into tissues of suckling rat pups via milk.
A risk to breastfed infants cannot be excluded. Breastfeeding should be discontinued during treatment with KXOSPATA and for at least 2 months after the last dose.
Fertility
There are no data on the effect of gilteritinib on human fertility.
Ability to influence the speed of reactions while driving or operating machinery.
Gilteritinib has a minor influence on the ability to drive and use machines. Dizziness has been reported in patients receiving KXOSPATA, and this should be taken into account when assessing the ability to drive or operate machinery (see section "Adverse reactions").
Method of administration and dosage
Treatment with Xospata should be initiated and monitored by a physician experienced in the use of anticancer therapies.
Prior to starting gilteritinib, patients with relapsed or refractory acute myeloid leukemia (AML) must have confirmed FMS-like tyrosine kinase 3 (FLT3) mutation (internal tandem duplication [ITD] or tyrosine kinase domain [TKD]) using a validated test.
Treatment with Xospata may be resumed in patients after allogeneic hematopoietic stem cell transplantation (HSCT) (see Table 2).
Dosage
The recommended starting dose is 120 mg gilteritinib (three 40 mg tablets) once daily.
Blood chemistry, including creatine phosphokinase, should be assessed prior to starting treatment, on day 15, and monthly throughout treatment (see section "Special instructions").
Electrocardiogram (ECG) should be performed prior to starting gilteritinib, on day 8 and day 15 of cycle 1, and prior to the start of each of the next three months of treatment (see sections "Method of administration and dosage" and "Adverse reactions").
Women of reproductive potential should be tested for pregnancy within seven days prior to initiating Xospata treatment (see sections "Special instructions" and "Pregnancy and breastfeeding").
Treatment should continue until clinical benefit from Xospata is no longer observed or until unacceptable toxicity occurs. Responses may be delayed; therefore, continuing treatment at the recommended dose for up to 6 months should be considered to allow sufficient time for an appropriate clinical response.
In the absence of response [patient has not achieved complete remission (CRc)] after 4 weeks of treatment, the dose may be increased to 200 mg (five 40 mg tablets) once daily, if well tolerated or clinically justified.
Dose modifications
Table 2
Recommendations for interruption, dose reduction, and discontinuation of Xospata in patients with relapsed or refractory AML
| Criteria |
Dosing recommendations for Xospata |
| Differentiation syndrome |
|
| Posterior reversible encephalopathy syndrome (PRES) |
|
| QTcF interval > 500 msec |
|
| QTcF prolongation > 30 msec on ECG on Day 8 of Cycle 1 |
|
| Pancreatitis |
|
| Other treatment-related toxicity grade 3 or higher |
|
| Planned HSCT |
|
a Grade 1 – mild toxicity, Grade 2 – moderate toxicity, Grade 3 – severe toxicity, Grade 4 – life-threatening toxicity.
b The daily dose may be reduced from 120 mg to 80 mg or from 200 mg to 120 mg.
sCRc is defined as the rate of remission of all CR (definition of CR see in section "Pharmacodynamics"), CRp [achieved CR except for incomplete platelet recovery (< 100 × 10^9/l)] and CRi (all CR criteria achieved except for incomplete hematological recovery with residual neutropenia < 1 × 10^9/l with or without full platelet recovery).
The medicinal product Xospata should be taken approximately at the same time each day. If a dose is missed or not taken at the usual time, the dose should be taken as soon as possible on the same day, and patients should return to their usual schedule the next day. If vomiting occurs after taking the product, patients should not take another dose but should return to their usual schedule the next day.
Elderly patients
Dose adjustment is not required for patients aged ≥ 65 years (see section "Pharmacokinetics").
Hepatic impairment
Dose adjustment is not required for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. The medicinal product Xospata is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C) as safety and efficacy have not been evaluated in this patient population (see section "Pharmacokinetics").
Renal impairment
Dose adjustment is not required for patients with mild, moderate or severe renal impairment (see sections "Special warnings and precautions for use" and "Pharmacological properties").
Method of administration
The medicinal product Xospata is intended for oral use.
The tablets may be taken with or without food.
The tablets should be swallowed whole with water and must not be split or crushed.
Children
The safety and efficacy of the medicinal product Xospata in children (under 18 years of age) have not yet been established.
There are no data on use in children. Due to in vitro binding to 5HT2B (see section "Interaction with other medicinal products and other forms of interaction"), there is a potential effect on cardiac development in patients under 6 months of age.
Overdose.
There is no specific antidote identified for the active substance of the medicinal product Xospata. In case of overdose, treatment with Xospata should be discontinued. Patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic and supportive treatment should be initiated considering the long elimination half-life of 113 hours.
Adverse reactions.
Summary of safety profile
The safety of the medicinal product Xospata was evaluated in clinical studies in 319 patients with relapsed or refractory AML who received at least one dose of gilteritinib (120 mg).
The most common adverse reactions with gilteritinib were increased alanine aminotransferase (ALT) (82.1%), increased aspartate aminotransferase (AST) (80.6%), increased alkaline phosphatase (68.7%), increased creatine phosphokinase (53.9%), diarrhea (35.1%), fatigue (30.4%), nausea (29.8%), constipation (28.2%), cough (28.2%), peripheral edema (24.1%), dyspnea (24.1%), dizziness (20.4%), hypotension (17.2%), limb pain (14.7%), asthenia (13.8%), arthralgia (12.5%), and myalgia (12.5%).
The most common serious adverse reactions were acute kidney injury (6.6%), diarrhea (4.7%), increased ALT (4.1%), dyspnea (3.4%), increased AST (3.1%), and hypotension (2.8%). Other clinically significant serious adverse reactions included differentiation syndrome (2.2%), QT interval prolongation on electrocardiogram (0.9%), and posterior reversible encephalopathy syndrome (0.6%).
Tabulated list of adverse reactions
Adverse reactions observed during clinical studies are listed below by frequency categories. Frequency categories are defined as follows: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.
Table 3
Adverse reactions
| Adverse drug reaction |
All toxicity grades, % |
Toxicity grade ≥3, % |
Frequency category |
| Immune system disorders |
|||
| Anaphylactic reaction |
1.3 |
1.3 |
common |
| Nervous system disorders |
|||
| Dizziness |
20.4 |
0.3 |
very common |
| Posterior reversible encephalopathy syndrome |
0.6 |
0.6 |
uncommon |
| Cardiac disorders |
|||
| QT interval prolongation on electrocardiogram |
8.8 |
2.5 |
common |
| Pericardial effusion |
4.1 |
0.9 |
common |
| Pericarditis |
1.6 |
0 |
common |
| Heart failure |
1.3 |
1.3 |
common |
| Vascular disorders |
|||
| Hypotension |
17.2 |
7.2 |
very common |
| Respiratory, thoracic and mediastinal disorders |
|||
| Cough |
28.2 |
0.3 |
very common |
| Dyspnea |
24.1 |
4.4 |
very common |
| Differentiation syndrome |
3.4 |
2.2 |
common |
| Gastrointestinal disorders |
|||
| Diarrhea |
35.1 |
4.1 |
very common |
| Nausea |
29.8 |
1.9 |
very common |
| Constipation |
28.2 |
0.6 |
very common |
| Hepatobiliary disorders |
|||
| Elevation of |
82.1 |
12.9 |
very common |
| Elevation of aspartate aminotransferase* |
80.6 |
10.3 |
very common |
| Musculoskeletal and connective tissue disorders |
|||
| Creatine phosphokinase increased* |
53.9 |
6.3 |
very common |
| Blood alkaline phosphatase increased* |
68.7 |
1.6 |
very common |
| Limb pain |
14.7 |
0.6 |
very common |
| Arthralgia |
12.5 |
1.3 |
very common |
| Myalgia |
12.5 |
0.3 |
very common |
| Skeletal and muscular pain |
4.1 |
0.3 |
common |
| Renal and urinary disorders |
|||
| Acute kidney injury |
6.6 |
2.2 |
common |
| General disorders and administration site conditions |
|||
| Fatigue |
30.4 |
3.1 |
very common |
| Peripheral edema |
24.1 |
0.3 |
very common |
| Asthenia |
13.8 |
2.5 |
very common |
| Malaise |
4.4 |
0 |
common |
* Frequency based on central laboratory data.
Description of individual adverse reactions
Differentiation syndrome
Of the 319 patients who received Xospata in clinical studies, 11 (3%) experienced differentiation syndrome. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells and can be life-threatening or fatal if not treated. Symptoms and clinical manifestations of differentiation syndrome in patients receiving Xospata included fever, dyspnea, pleural effusion, pericardial effusion, pulmonary edema, hypotension, rapid weight gain, peripheral edema, rash, and renal dysfunction. In some cases, concomitant acute febrile neutrophilic dermatosis was observed. Differentiation syndrome occurred as early as one day and within up to 82 days after initiation of Xospata, and was observed with or without concomitant leukocytosis. Of the 11 patients who developed differentiation syndrome, 9 (82%) recovered after treatment or after discontinuation of Xospata. Recommendations for suspected differentiation syndrome are provided in the sections "Dosage and administration" and "Special warnings and precautions for use".
PRES syndrome
Of the 319 patients who received Xospata in clinical studies, 0.6% had posterior reversible encephalopathy syndrome (PRES). PRES syndrome is a rare reversible neurological disorder that may present with rapidly developing symptoms, including seizures, headache, confusion, visual and neurological disturbances, with or without associated hypertension. Symptoms resolved after discontinuation of treatment (see sections "Dosage and administration" and "Special warnings and precautions for use").
QT interval prolongation
Among 317 patients who received gilteritinib at a dose of 120 mg and in whom QTc interval duration was compared to baseline in clinical studies, 4 patients (1%) had QTcF > 500 msec. Additionally, across all doses, 12 patients (2.3%) with relapsed/refractory AML had a maximum post-baseline QTcF interval > 500 msec (see sections "Dosage and administration", "Special warnings and precautions for use", and "Pharmacological properties").
Reporting suspected adverse reactions
Reporting of adverse reactions after marketing authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life. 4 years.
Storage conditions. Store at a temperature not exceeding 30 °C.
Store in the original packaging in a place protected from light.
Packaging. 21 film-coated tablets in a blister; 4 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
Delpharm Meppel B.V., the Netherlands / Delpharm Meppel B.V., the Netherlands.
Manufacturer's address and place of business.
Hogemaat 2, 7942 JG Meppel, the Netherlands / Hogemaat 2, 7942 JG Meppel, the Netherlands.
Marketing authorization holder.
Astellas Pharma Europe B.V., the Netherlands / Astellas Pharma Europe B.V., the Netherlands.
Address of the marketing authorization holder.
Sylviusweg, 62, 2333 BE Leiden, the Netherlands / Sylviusweg, 62, 2333 BE Leiden, the Netherlands.