Neopax®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Neopax® (Neopax®)

Composition:

Active substance: imatinib;

1 film-coated tablet contains 100 mg or 400 mg of imatinib (as imatinib mesylate);

Excipients: lactose monohydrate, corn starch, hydroxypropylcellulose, microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;

Film-coating composition: Opadry White (containing polyvinyl alcohol, titanium dioxide (E 171), macrogol 3000, talc), iron oxide yellow (E 172), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics:

100 mg tablets: round, slightly biconvex, film-coated tablets of orange-brown color with a break line on one side and beveled edges;

400 mg tablets: elongated, biconvex, film-coated tablets of orange-brown color.

Pharmacotherapeutic group. Antineoplastic agents. BCR-ABL tyrosine kinase inhibitors. Imatinib. ATC code L01E A01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Imatinib is a small molecule protein tyrosine kinase inhibitor that potently inhibits the activity of BCR-ABL tyrosine kinase (TK), as well as several receptor TKs: Kit, stem cell factor receptor (SCF receptor) encoded by the c-Kit proto-oncogene, discoidin domain receptors (DDR1 and DDR2), colony-stimulating factor (CSF-1R), and platelet-derived growth factor alpha- and beta-receptors (PDGFR-alpha and PDGFR-beta). Imatinib may also inhibit cellular activity mediated by activation of these receptor kinases.

Pharmacodynamic effects

Imatinib is a protein tyrosine kinase inhibitor that strongly suppresses BCR-ABL tyrosine kinase activity in vitro, at the cellular level, and in vivo. The active substance selectively inhibits proliferation and induces apoptosis in BCR-ABL+ cell lines, as well as in freshly isolated leukemic cells from patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) and acute lymphoblastic leukemia (ALL).

In vivo, the active substance demonstrates antitumor activity as a single agent in animal models using BCR-ABL+ tumor cells.

Imatinib is also an inhibitor of receptor tyrosine kinases for platelet-derived growth factor (PDGF), PDGF-R, and stem cell factor (SCF), c-Kit, and it also inhibits PDGF- and SCF-mediated cellular activity. In vitro, imatinib inhibits proliferation and induces apoptosis in cells of gastrointestinal stromal tumors (GISTs) expressing activated Kit mutations. Significant activation of PDGF receptor or BCR-ABL protein tyrosine kinase due to fusion with various partner proteins or excessive PDGF production has been implicated in the pathogenesis of myelodysplastic/myeloproliferative neoplasms (MDS/MPN), hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL), and dermatofibrosarcoma protuberans (DFSP). Imatinib inhibits signal transduction and cell proliferation caused by dysregulated PDGFR and ABL kinase activity.

Clinical studies in CML

The efficacy of imatinib is based on overall hematologic and cytogenetic response to treatment and progression-free survival. Except for newly diagnosed chronic phase CML, there are no controlled studies demonstrating a positive clinical effect in terms of improvement of disease-related symptoms or increased survival.

Three large international open-label, uncontrolled phase II studies were conducted in patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the following disease stages: late chronic phase, blast crisis, accelerated phase, other Ph+ leukemias, or chronic phase CML after failure of prior therapy with alpha-interferon (IFN). One large open-label, multicenter, international randomized phase III study was conducted in patients with newly diagnosed Ph+ CML. In addition, pediatric patients were treated in two phase I studies and one phase II study.

In all clinical trials, 38–40% of patients were aged ≥60 years, and 10–12% were aged ≥70 years.

Chronic phase, newly diagnosed. This phase III study in adult patients allowed comparison of treatment with imatinib monotherapy versus combination therapy with alpha-interferon (IFN) plus cytarabine (Ara-C). Patients who had suboptimal response (lack of complete hematologic response by month 6, rising white blood cell count, or lack of complete cytogenetic response by month 24), lost response (loss of complete hematologic or complete cytogenetic response), or demonstrated severe treatment intolerance were permitted to cross over to the alternative treatment arm. In the imatinib group, patients received 400 mg of the drug daily. In the interferon group, patients were treated with a target dose of interferon 5 million IU/m²/day subcutaneously in combination with subcutaneous Ara-C 20 mg/m²/day for 10 days per month.

A total of 1106 patients were randomized, with 553 patients in each group. Baseline characteristics were well balanced between the two groups. The median age was 51 years (range 18–70 years), and 21.9% of patients were aged ≥60 years. 59% were male and 41% female; 89.9% were Caucasian and 4.7% were Black. Seven years after enrollment of the last patient, the median duration of first-line therapy was 82 months in the imatinib group and 8 months in the interferon group. The median duration of second-line therapy with imatinib was 64 months. Overall, in patients receiving first-line imatinib therapy, the mean daily dose was 406 ± 76 mg. The primary efficacy endpoint of the study was progression-free survival. Progression was defined as any of the following events: progression to accelerated phase or blast crisis, death, loss of complete hematologic response or complete cytogenetic response, or increase in white blood cell count in patients who did not achieve complete hematologic response despite adequate therapy.

Complete cytogenetic response, hematologic response, molecular response (assessment of minimal residual disease), time to accelerated phase or blast crisis, and overall survival are key secondary endpoints. Data on treatment response are presented in Table 1.

Table 1

Therapeutic effect of the investigational treatment in patients with newly diagnosed CML (data at 84 months)

The determination of complete hematological response, major and complete cytogenetic response rates to first-line drug therapy was performed using the Kaplan-Meier method, where subjects who did not respond to treatment were censored at the time of their last assessment. Based on this method, the cumulative treatment effect of first-line imatinib therapy between 12 and 84 months was estimated to improve to the following levels: CHR – from 96.4% to 98.4%, MCyR – from 69.5% to 87.2%, respectively.

During seven years of follow-up, 93 (16.8%) disease progression events were recorded in the imatinib treatment groups: 37 (6.7%) cases of blast crisis or accelerated phase development, 31 cases of loss of CCyR, 15 (2.7%) cases of loss of CHR or increased white blood cell count, and 10 (1.8%) patient deaths unrelated to CML. In the IFN+Ara-C treatment groups, 165 (29.8%) disease progression events were recorded, of which 130 occurred during first-line IFN+Ara-C therapy.

The predicted percentage of patients without progression to accelerated phase or blast crisis at 84 months was significantly higher in the imatinib groups compared to the IFN group (92.5% vs. 85.1%, p<0.001). The annual rate of progression to accelerated phase or blast crisis decreased progressively over time and was less than 1% during the fourth and fifth years of therapy. The estimated progression-free survival rate at 84 months was 81.2% in the imatinib group and 60% in the control group (p<0.001). The annual rate of any type of CML progression also decreased over time.

Overall mortality in the imatinib and IFN+Ara-C groups was 71 (12.8%) and 85 (15.4%) patients, respectively. The overall predicted survival rate at 84 months was 86.4% (95% CI: 83, 90) in the imatinib randomized groups versus 83.3% (95% CI: 80, 87) in the IFN+Ara-C groups (p=0.073, log-rank test). This endpoint was significantly influenced by the high crossover rate from IFN+Ara-C to imatinib. Subsequent evaluation of imatinib's survival benefit in chronic-phase newly diagnosed CML was performed by retrospective analysis of the aforementioned imatinib data combined with primary data from another study conducted under a similar Phase III regimen using IFN+Ara-C (n=325). The analysis demonstrated a significant survival advantage for imatinib over IFN+Ara-C (p<0.001); during 42 months of follow-up, 47 (8.5%) patients died in the imatinib groups versus 63 (19.4%) in the IFN+Ara-C groups.

Long-term outcomes in the imatinib group were significantly influenced by the level of cytogenetic and molecular response to therapy. Considering the predicted rate of 96% (93%) of patients achieving MCyR (CCyR) at 12 months who remained free of disease progression to accelerated phase or blast crisis at 84 months, only 81% of patients without CCyR at 12 months remained progression-free at 84 months (p<0.001 overall, p=0.25 between MCyR and CCyR). In patients with at least a 3-log reduction in Bcr-Abl transcript levels at 12 months, the probability of remaining in remission without progression to accelerated phase/blast crisis was 99% at 84 months. Similar results were observed during stepwise 18-month analyses.

In this study, dose escalation from 400 mg to 600 mg daily, and subsequently from 600 mg to 800 mg daily, was permitted. After 42 months of follow-up, 11 patients experienced a decrease (within 4 weeks) in cytogenetic response to therapy. Of these 11 patients, 4 had their dose increased to 800 mg daily; cytogenetic response was restored in 2 of the 4 (1 partial and 1 complete, with the latter also achieving a molecular response). Among the 7 patients whose dose was not escalated, only one achieved restored complete cytogenetic response. The incidence of certain adverse reactions was higher in patients receiving the 800 mg daily dose compared to the population prior to dose escalation (n=551). The most common adverse events included gastrointestinal hemorrhage, conjunctivitis, and elevated transaminase or bilirubin levels. The frequency of other adverse effects was similar or lower.

Chronic phase, prior interferon therapy failure. Drug therapy was administered to 532 adult patients starting at a dose of 400 mg. Patients were categorized into three main groups: lack of hematological response (29%), lack of cytogenetic response (35%), or intolerance to interferon (36%). Patients were in late chronic-phase CML and had previously received a median of 14 months of IFN therapy at doses ≥25×10⁶ IU/week; the median time from diagnosis was 32 months. The primary efficacy endpoint was the rate of cytogenetic response to treatment (major and complete response, 0–35% Ph+ metaphases in bone marrow).

In this study, 65% of patients achieved a major cytogenetic response, which was complete in 53% (confirmed in 43%) of patients (see Table 2). Complete hematological response was achieved in 95% of patients.

Accelerated phase. A total of 235 adult patients in accelerated phase were enrolled in the trial. The first 77 patients received an initial dose of 400 mg, with subsequent dose escalation allowed per protocol. The remaining 158 patients initiated therapy at 600 mg.

The primary efficacy endpoint was the rate of hematological response, defined as complete hematological response, absence of leukemia (i.e., no blasts in bone marrow or blood, but without full normalization of peripheral blood counts as in complete response), or return to chronic-phase CML. Confirmed hematological response was observed in 71.5% of patients (see Table 2). Importantly, 27.7% of patients also achieved a major cytogenetic response. Complete response was achieved in 20.4% (confirmed in 16%) of patients. For patients receiving the 600 mg dose, the median duration of remission and overall survival is currently estimated at 22.9 and 42.5 months, respectively.

Myeloid blast crisis. A total of 260 patients with myeloid blast crisis were enrolled. Of these, 95 (37%) had previously received chemotherapy for accelerated phase or blast crisis (previously treated), and 165 (63%) were treatment-naïve. The first 37 patients received an initial dose of 400 mg, with subsequent dose escalation permitted per protocol. The remaining 223 patients initiated therapy at 600 mg.

The primary efficacy endpoint was the rate of hematological response, defined as complete hematological response, absence of leukemia signs, or return to chronic-phase CML with criteria similar to accelerated phase. In this study, 31% of patients achieved a hematological response (36% in previously untreated patients vs. 22% in previously treated). Response rates were higher in patients receiving 600 mg (33%) compared to those receiving 400 mg (16%, p = 0.0220). Currently, the median survival for previously untreated patients and those previously treated is estimated at 22.9 and 42.5 months, respectively.

Lymphoid blast crisis. A limited number of such patients (n=10) were enrolled in the Phase I study. Hematological response within 2–3 months was observed in 70% of cases.

Table 2

Response to drug therapy in adult patients with CML

Children. Phase I dose-escalation clinical study enrolled 26 children aged <18 years with CML in chronic phase (n=11), in blast crisis or with Ph+ acute leukemia (n=15). This patient population had previously received intensive therapy: 46% had a history of bone marrow transplantation (BMT) and 73% had received combination chemotherapy. Patients received imatinib doses of 260 mg/m²/day (n=5), 340 mg/m²/day (n=9), 440 mg/m²/day (n=7), and 570 mg/m²/day (n=5). Out of the total, cytogenetic data were available for analysis in only 9 patients with chronic-phase CML; 4 (44%) and 3 (33%) patients achieved complete and partial cytogenetic response, respectively, with a major cytogenetic response (MCyR) rate of 77%.

Overall, 51 children with newly diagnosed chronic-phase CML were enrolled in a Phase II, open-label, multicenter, uncontrolled study. Patients received 340 mg/m²/day of imatinib continuously due to the absence of dose-limiting toxicity. After 8 weeks of treatment in children with newly diagnosed CML, a rapid response to therapy was observed: major cytogenetic response (MCyR) was 78%. This higher MCyR rate was associated with complete cytogenetic response (CCyR) in 65%, which is similar to the results observed in adult patients. Additionally, an additional 16% of patients who achieved MCyR had a complete molecular response (CMR) with a bcr-abl transcript level of 81%. In the majority of patients who achieved CCyR between 3 and 10 months of treatment, the median time to response was estimated at 5.6 months (based on Kaplan-Meier method).

Clinical studies of Ph+ ALL (Philadelphia chromosome-positive acute lymphoblastic leukemia)

Newly diagnosed Ph+ ALL. In a controlled study (ADE 10) evaluating the efficacy of imatinib compared to induction chemotherapy, 55 newly diagnosed patients aged over 55 years received imatinib monotherapy. As a result, a significantly higher rate of complete hematologic response was achieved compared to chemotherapy (96.3% vs. 50%; p=0.0001). In cases where conservative therapy with imatinib was administered to patients who poorly responded or did not respond at all to chemotherapy, 9 out of 11 patients (81.8%) achieved complete hematologic response. The clinical effect was associated with a significant reduction in bcr-abl transcript levels in the imatinib group compared to the chemotherapy group after 2 weeks of treatment (p=0.02). After induction, all patients received imatinib in combination with consolidation chemotherapy (see Table 3), and bcr-abl transcript levels were similar in both groups after 8 weeks. As anticipated at the study design stage, no difference was observed in remission duration, event-free survival, or overall survival. However, patients achieving complete molecular response and minimal residual disease had better outcomes in terms of remission duration (p=0.01) and event-free survival.

During four uncontrolled clinical trials (AAU02, ADE04, AJP01, and AUS01), a population of 211 newly diagnosed Ph+ ALL patients showed results consistent with the above. Treatment with imatinib in combination with induction chemotherapy (see Table 3) resulted in a hematologic response rate of 93% (147 out of 158 evaluated patients) and a major cytogenetic response rate of 90% (19 out of 21 evaluated patients). Complete molecular response was achieved in 48% (49 out of 102 evaluated patients). Event-free survival (EFS) and overall survival (OS) in two studies (AJP01 and AUS01) exceeded 1 year, which is superior to historical monitoring data (EFS p<0.001; OS p<0.0001).

Table 3

Chemotherapy regimen in combination with imatinib

Pediatric patients

In the I2301 study, 93 patients (aged 1 to 22 years) with Ph+ ALL were enrolled in an open-label, multicenter, sequential cohort, non-randomized phase III trial and received imatinib (340 mg/m²/day) in combination with intensive chemotherapy following induction therapy. Imatinib was administered with interruptions in cohorts 1–5, with increasing duration and earlier initiation of imatinib from cohort to cohort; cohort 1 received the lowest intensity, and cohort 5 received the highest intensity of imatinib (longest duration in days with continuous daily dosing of imatinib during the initial chemotherapy cycles). Continuous daily administration of imatinib from the start of treatment in combination with chemotherapy in cohort 5 patients (n=50) improved 4-year event-free survival (EFS) compared to a historical control group (n=120) who received standard chemotherapy without imatinib (69.6% vs. 31.6%, respectively). The estimated 4-year overall survival (OS) in cohort 5 patients was 83.6% compared to 44.8% in previous control groups. 20 out of 50 (40%) patients in cohort 5 underwent hematopoietic stem cell transplantation.

Table 4

Chemotherapy regimen in combination with imatinib in study I2301

G-CSF – granulocyte colony-stimulating factor, VP-16 – etoposide, MTX – methotrexate, IV – intravenous, SC – subcutaneous, IT – intrathecal, PO – oral, IM – intramuscular, ARA-C – cytarabine, CPM – cyclophosphamide, VCR – vincristine, DEX – dexamethasone, DAUN – daunorubicin, L-ASP – L-asparaginase, PEG-ASP – PEG asparaginase, MESNA – 2-mercaptoethane sulfonate sodium, III – or until MTX level <0.1 µM.

The AIT07 study was a multicenter, open-label, randomized, phase II/III trial that included 128 patients (aged 1 to 18 years) who received imatinib in combination with chemotherapy. Safety data from this study are highly likely to reflect the safety profile of imatinib in patients with Ph+ ALL.

Relapsed/Refractory Ph+ ALL. In patients with relapsed or refractory Ph+ ALL treated with imatinib monotherapy, a response to treatment was observed in 53 of 411 patients, major cytogenetic response in 23%, and hematologic response in 30% (9% complete). Note: 353 of the 411 patients were treated in expanded access programs where data on primary response to therapy were not collected. The median time to progression in the overall population (411 patients) with relapsed or refractory Ph+ ALL was 2.6–3.1 months, and the median overall survival ranged from 4.9 to 9 months. Similar results were obtained in a reanalysis including only patients aged 55 years and older.

Clinical studies in MDS/MPS

Clinical experience with imatinib in this condition is limited and based on hematologic and cytogenetic response rates. There are no clinical trials demonstrating a significant clinical benefit of drug therapy or improved patient survival. In an open-label, multicenter phase II clinical trial (Study B2225), imatinib was tested in various patient populations with life-threatening diseases associated with Abl, Kit, or PDGFR protein tyrosine kinases. Seven patients with MDS/MPS received 400 mg of imatinib daily. Three of them achieved CHR and one achieved PR. Among the four patients with identified PDGFR gene rearrangement, three achieved hematologic response (two CHR and one PR). Patient ages ranged from 20 to 72 years.

A clinical registry (Study L2401) was established to collect long-term safety and efficacy data in patients with myeloproliferative neoplasms with PDGFR-β rearrangement who were treated with imatinib. Twenty-three patients enrolled in this registry received imatinib at a median daily dose of 264 mg (range: 100 to 400 mg) for a median duration of 7.2 years (range: 0.1 to 12.7 years). Due to the observational nature of this registry, hematologic, cytogenetic, and molecular assessments were available for 22, 9, and 17 of the 23 enrolled patients, respectively. Assuming patients with missing data did not achieve a clinical response, CHR was observed in 20/23 (87%) patients, CCyR in 9/23 (39.1%), and molecular response (MR) in 11/23 (47.8%) patients. When response rates were calculated among patients with at least one confirmed assessment, the response rates for CHR, CCyR, and MR were 20/22 (90.9%), 9/9 (100%), and 11/17 (64.7%), respectively.

Additionally, 24 patients with MDS/MPS were reported in 13 publications. Twenty-one patients received 400 mg of imatinib daily, while lower doses were administered to the remaining patients. PDGFR gene rearrangement was identified in 11 patients, 9 of whom achieved CHR and 1 achieved PR. Patient ages ranged from 2 to 79 years. Recent publications provided updated information on 6 of these 11 patients, all of whom remained in cytogenetic remission (follow-up period 32–38 months). Another publication reported long-term follow-up data on 12 patients with MDS/MPS and PDGFR gene rearrangement (5 patients from Study B2225). These patients received imatinib for a median of 47 months (range: 24 days to 60 months). Six of them have been followed for at least 4 years. Rapid CHR was observed in 11 patients, complete cytogenetic normalization in 10, and reduction or complete disappearance of transcript levels. Hematologic and cytogenetic responses occurred after a median of 49 months (range: 19–60) and 47 months (range: 16–59), respectively. Median overall survival from diagnosis was 65 months (range: 25–234 months). Imatinib use in patients without genetic translocations did not lead to significant clinical outcomes.

There are no clinical trials in children with MDS/MPS. Information on 5 pediatric patients with MDS/MPS associated with PDGFR gene rearrangement was published in 4 reports. Patient ages ranged from 3 months to 4 years; imatinib was administered at a dose of 50 mg or between 92.5 mg/m² and 340 mg/m² daily. All patients achieved complete hematologic response, cytogenetic and/or clinical response.

Clinical studies in patients with HES/CEL

An open-label, multicenter, phase II clinical trial (Study B2225) evaluated imatinib in various patient populations with life-threatening diseases associated with Abl, Kit, or PDGFR protein tyrosine kinases. Fourteen patients with HES/CEL received imatinib at doses ranging from 100 mg to 1000 mg daily. Additionally, 162 patients with HES/CEL received imatinib at doses from 75 mg to 800 mg daily, as reported in 35 published case reports and case series. Cytogenetic abnormalities were assessed in 117 of the total 176 patients. The FIP1L1-PDGFRα hybrid kinase was detected in 61 of these 117 patients. In three additional published case reports, four more HES patients tested positive for FIP1L1-PDGFRα. All 65 patients with positive FIP1L1-PDGFRα hybrid kinase achieved a sustained hematologic response within one month (range: 1+ to 44+ months, censored at time of reporting). According to a recent publication, 21 of these 65 patients also achieved complete molecular remission, with a median follow-up of 28 months (range: 13–67 months). Patient ages ranged from 25 to 72 years. Furthermore, other case reports described improvement in symptoms and organ dysfunction, including cardiac, nervous system, skin/subcutaneous tissue, respiratory system/chest/mediastinum, musculoskeletal/connective tissue/vascular, and gastrointestinal tract involvement.

Controlled trials in children with HES/CEL have not been conducted. Three publications reported three (3) patients with HES and CEL associated with PDGFR receptor gene rearrangements. Patient ages ranged from 2 to 16 years; imatinib was administered at 300 mg/m² daily or in the dose range of 200–400 mg daily. All patients achieved complete hematologic response, complete cytogenetic response, and/or complete molecular response.

Clinical studies in patients with unresectable and/or metastatic GIST

One open-label, randomized, uncontrolled, international phase II trial was conducted in patients with unresectable or metastatic malignant GIST. A total of 147 patients were enrolled and randomized to receive imatinib at a dose of 400 mg or 600 mg orally once daily for up to 36 months. Patients were aged 18 to 83 years and had a histologically confirmed diagnosis of Kit-positive malignant GIST that was unresectable and/or metastatic. Immunohistochemical analyses using Kit antibodies (A-4502, rabbit polyclonal antisera, 1:100; DAKO Corporation, Carpinteria, California) were routinely performed using the avidin-biotin-peroxidase complex method following antigen unmasking.

Initial evidence of efficacy was based on objective response rate. Tumors had to be measurable in at least one disease site; response assessments were based on Southwest Oncology Group (SWOG) criteria. Results are presented in Table 5.

Table 5

Best tumor response in Study STIB2222 (GIST)

There were no differences in response rates between the two treatment groups. A substantial number of patients who had stable disease at the time of the interim analysis achieved partial remission with longer-term treatment (median follow-up period was 31 months). The median time to response was 13 weeks (95% CI 12–23). The median time to treatment failure in patients was 122 weeks (95% CI 106–147), compared to 84 weeks (95% CI 71–109) in the overall study population. Median overall survival has not been reached. The Kaplan-Meier estimate of survival at 36 months was 68%.

In two clinical trials (study B2222 and intergroup study S0033), the daily dose of imatinib was increased to 800 mg in patients who progressed on lower daily doses (400 mg or 600 mg). A total of 103 patients had their daily dose increased to 800 mg for an overall clinical benefit rate of 26%; 6 patients achieved partial remission and 21 achieved disease stabilization following dose escalation. Available safety data indicate that dose escalation to 800 mg daily in patients who progressed on lower doses (400 mg or 600 mg daily) does not affect the safety profile of imatinib.

Clinical trials in patients with GIST receiving adjuvant therapy

In a multicenter, double-blind, long-term, placebo-controlled phase III trial (Z9001) involving 773 patients, imatinib was evaluated as adjuvant therapy. The age of these patients ranged from 18 to 91 years. Patients included in the study had a histological diagnosis of primary GIST, expressed Kit protein by immunohistochemical testing, and had a tumor size ≥ 3 cm in maximum dimension, with complete resection of the primary GIST within 14–70 days prior to registration. After resection of the primary GIST, patients were randomized to one of two study groups: imatinib 400 mg daily or placebo for one year.

The primary endpoint of the study was recurrence-free survival (RFS), defined as the time from the date of randomization to the date of recurrence or death from any cause.

Imatinib significantly improved RFS, with 75% of patients remaining recurrence-free at 38 months of imatinib treatment compared to 20 months in the placebo group (95% CI [30 – not evaluable]; [14 – not evaluable], respectively); (hazard ratio – 0.398 [0.259–0.610], p <0.0001). Over one year, overall RFS was significantly improved in the imatinib group (97.7%) compared to placebo (82.3%) (p <0.0001). Thus, the risk of recurrence was reduced by approximately 89% compared to placebo (hazard ratio – 0.113 [0.049–0.264]).

The risk of recurrence in patients after surgical resection of primary GIST was assessed by retrospective analysis based on the following prognostic factors: tumor size, mitotic index, and tumor location. Mitotic index data were available for 556 out of 713 patients who started treatment. Results of subgroup analysis according to risk classification by the U.S. National Institutes of Health and the Armed Forces Institute of Pathology are presented in Table 6. No benefit was observed in the low- and very low-risk groups. There was also no benefit in overall survival.

Table 6

Summary of RFS analysis in study Z9001 according to risk classification by the U.S. National Institutes of Health and the Armed Forces Institute of Pathology

* Full follow-up period; not defined.

In the course of the second multicenter open-label phase III study (SSG XVIII/AIO), treatment with imatinib at a dose of 400 mg daily for 12 months was compared with a 36-month treatment period in patients following surgical resection of GISTs with one of the following risk factors: tumor diameter >5 cm and mitotic index >5/50 high-power fields, or tumor diameter >10 cm and any mitotic index, or tumor of any size with mitotic index >10/50 high-power fields, or tumors with rupture into the abdominal cavity. Overall, 397 patients consented to participate in the study and were randomized (199 patients to the 12-month treatment group and 198 patients to the 36-month treatment group); the median age was 61 years (range 22 to 84 years). The median follow-up period was 54 months (from date of randomization to date of data cutoff), with a total time between the first randomized patient and data cutoff of 83 months.

The primary endpoint of the study was recurrence-free survival (RFS).

Treatment with imatinib for 36 months resulted in significantly longer RFS compared to 12 months of imatinib treatment (with a overall hazard ratio (HR) = 0.46 [0.32, 0.65], p <0.0001) (see Table 7).

Furthermore, treatment with imatinib for 36 months resulted in significantly longer overall survival (OS) compared to 12 months of imatinib treatment (HR = 0.45 [0.22, 0.89], p <0.0187) (see Table 7).

Longer treatment duration (>36 months) may delay the onset of subsequent recurrences; however, the impact of this finding on overall survival remains unknown.

The total number of deaths was 25 in the 12-month treatment group and 12 in the 36-month treatment group.

In the analysis of patients who started treatment, i.e., the intent-to-treat population, treatment with imatinib for 36 months showed better outcomes than the 12-month treatment group. In a pre-planned subgroup analysis by mutation type, the HR for RFS in the 36-month treatment group for patients with exon 11 mutations was 0.35 [95% CI: 0.22; 0.56]. No conclusions could be drawn for other subgroups with less common mutations due to the low number of observed events.

Table 7

Imatinib treatment for 12 months versus 36 months (SSGXVIII/AIO study)

Controlled clinical studies in children with c-Kit positive GISTs have not been conducted. Seven publications reported on 17 pediatric patients with GISTs (with or without Kit and PDGFRA mutations). These patients ranged in age from 8 to 18 years and were treated with imatinib as adjuvant or metastatic therapy at doses ranging from 300 to 400 mg per day. In most children treated for GISTs, there was insufficient data confirming c-Kit or PDGFRA mutations, which could have led to mixed clinical outcomes.

Clinical studies in patients with DFSP

One open-label, multicenter, phase II clinical trial (study B2225) was conducted in 12 patients with DFSP who received imatinib at a dose of 800 mg per day. The age of DFSP patients ranged from 23 to 75 years; the DFSPs were metastatic, locally recurrent after primary resection, and were not amenable to further surgical resection at the time of study entry. Initial evidence of efficacy was based on objective response rate. Of the 12 patients enrolled in the study, 9 responded to treatment: 1 had a complete response and 8 had partial responses. Three patients with partial responses later showed no evidence of disease following surgical intervention. The median duration of therapy in study B2225 was 6.2 months, with a maximum duration of 24.3 months. Five published case reports described an additional 6 DFSP patients treated with imatinib, whose ages ranged from 18 months to 49 years. Adult patients reported in the literature were treated with imatinib at a dose of 400 mg (4 cases) or 800 mg (1 case) per day. Treatment response was observed in 5 patients: 3 had complete responses and 2 had partial responses. The median duration of therapy in these publications ranged from 4 weeks to over 20 months. The t(17;22)[(q22;q13)] translocation or its gene product was present in nearly all patients who responded to imatinib therapy.

Controlled clinical studies in children with DFSP have not been conducted. In three publications, gene rearrangements associated with DFSP and the PDGFR receptor were reported in 5 pediatric patients. These patients ranged in age from newborns to 14 years and were treated with imatinib at a dose of 50 mg per day or in the dose range of 400 to 520 mg/m² per day. All patients achieved partial and/or complete response to treatment.

Pharmacokinetics.

Pharmacokinetics of imatinib

Imatinib pharmacokinetics were evaluated following doses ranging from 25 to 1000 mg. Pharmacokinetic profiles were analyzed on Day 1 and on Day 7 or Day 28, when steady-state plasma concentrations of imatinib were achieved.

Absorption

The absolute bioavailability of imatinib is approximately 98%. The coefficient of variation for imatinib plasma AUC is high among patients following oral administration. When administered with a high-fat meal compared to fasting, there is a slight reduction in the extent of absorption (an 11% decrease in Cmax and a 1.5-hour prolongation of tmax) and a minor decrease in AUC (7.4%) compared to fasting. The effect of prior gastrointestinal surgery on drug absorption has not been studied.

Distribution

In vitro data indicate that at clinically relevant concentrations, approximately 95% of imatinib is bound to plasma proteins (primarily albumin and acid α-glycoprotein, to a lesser extent lipoproteins).

Biotransformation

The major circulating metabolite of imatinib is the N-demethylated piperazine derivative, which in vitro exhibits pharmacological activity similar to that of the parent compound. Plasma AUC values for this metabolite are only 16% of those for imatinib. Binding of the N-demethylated metabolite to plasma proteins is similar to that of the parent drug.

Imatinib and its N-demethylated metabolite together account for approximately 65% of circulating radioactivity (AUC(0-48)). The remainder of circulating radioactivity consists of several minor metabolites.

In vitro studies have shown that CYP3A4 is the primary human P450 enzyme responsible for the biotransformation of imatinib. Among potential concomitant medications (acetaminophen, acyclovir, allopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, penicillin V), only erythromycin (IC50 50 µM) and fluconazole (IC50 118 µM) demonstrated inhibitory effects on imatinib metabolism that may have clinical significance.

In vitro studies indicate that imatinib can act as a competitive inhibitor of marker substrates for CYP2C9, CYP2D6, and CYP3A4/5. The Ki values in human liver microsomes were 27, 7.5, and 7.9 µmol/L, respectively. The maximum plasma concentration of imatinib in patients is 2–4 µmol/L; thus, inhibition of CYP2D6 and/or CYP3A4/5 metabolism of co-administered drugs is possible. Imatinib does not interfere with the biotransformation of 5-fluorouracil but inhibits paclitaxel metabolism via competitive inhibition of CYP2C8 (Ki = 34.7 µM). This Ki value is much higher than the expected plasma levels in patients receiving imatinib; therefore, drug interactions are not expected when imatinib is co-administered with 5-fluorouracil or paclitaxel.

Elimination

Following oral administration of 14C-labeled imatinib, approximately 81% of the dose is excreted within 7 days, with 68% in feces and 13% in urine. Approximately 25% of the dose is excreted unchanged (20% in feces and 5% in urine). The remainder is excreted as metabolites.

Plasma pharmacokinetics

The elimination half-life (t½) after oral administration in healthy volunteers is approximately 18 hours, supporting the acceptability of once-daily dosing. A linear relationship between AUC and dose is observed over the dose range of 25 to 1000 mg. With repeated dosing, imatinib pharmacokinetics remain unchanged, and drug accumulation at steady state is 1.5 to 2.5 times the initial level.

Pharmacokinetics in patients with GIST

In patients with GIST, exposure to imatinib is 1.5 times higher than in patients with CML when administered at the same dose (400 mg per day). Based on prior population pharmacokinetic analysis in GIST patients, three variables (albumin, white blood cell count, and bilirubin) were found to have a statistical relationship with imatinib pharmacokinetics. Decreased albumin levels and higher white blood cell counts were associated with reduced clearance (CL/F). However, these factors are not considered clinically significant enough to require dose adjustments. In this patient population, the presence of liver metastases may potentially lead to hepatic insufficiency and reduced metabolism.

Population pharmacokinetic analysis

Based on population pharmacokinetic data in CML patients, age has a minor effect on volume of distribution (a 12% increase in patients >65 years). This change is not considered clinically significant. Body weight has a minor effect on imatinib clearance: for patients weighing 50 kg, the average clearance is 8.5 L/hour, increasing to 11.8 L/hour for patients weighing 100 kg. These changes are not sufficient to justify dose adjustments based on body weight. Imatinib pharmacokinetics are independent of sex and age.

Pharmacokinetics in children and adolescents

As in adults, imatinib is rapidly absorbed in children after oral administration in both phases of studies. The recommended pediatric dosing is 260 and 340 mg/m²/day, which corresponds clinically to 400 mg and 600 mg doses in adults. Comparison of AUC(0-24) on Day 8 versus Day 1 at a dose of 340 mg/m²/day showed a 1.7-fold accumulation after repeated dosing.

Based on a pooled population pharmacokinetic analysis in pediatric patients with hematologic disorders (CML, Ph+ ALL, or other hematologic conditions treated with imatinib), imatinib clearance increases with increasing body surface area (BSA). After adjusting for BSA, other demographic factors such as age, body weight, and body mass index had no clinically significant effect on imatinib exposure. The analysis confirmed that exposure in children receiving 260 mg/m² once daily (not exceeding 400 mg once daily) or 340 mg/m² once daily (not exceeding 600 mg once daily) is comparable to that in adults receiving imatinib 400 mg or 600 mg once daily.

Patients with organ dysfunction

Imatinib and its metabolites are minimally excreted by the kidneys. Since renal clearance of imatinib is low, overall clearance is only slightly reduced in patients with renal impairment. The increase is approximately 1.5 to 2-fold, corresponding to a 1.5-fold increase in plasma levels of alpha-1 acid glycoprotein, to which imatinib is strongly bound. The clearance of unbound imatinib is likely similar in patients with renal impairment and those with normal renal function, as renal excretion represents only a minor elimination pathway for imatinib.

Although pharmacokinetic study results showed considerable variability, the mean exposure to imatinib was not increased in patients with varying degrees of hepatic dysfunction compared to patients with normal liver function.

Clinical characteristics.

Indications.

Neopax® is indicated for the treatment of:

• adults and children with newly diagnosed chronic myeloid leukemia (CML) positive for the Philadelphia chromosome (Ph+) (BCR-ABL), for whom bone marrow transplantation is not considered as first-line therapy;
• adults and children with Ph+ CML in chronic phase after failure of therapy with alpha-interferon, or in accelerated phase or blast crisis;
• adults and children with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), as part of chemotherapy;
• adults with relapsed or refractory Ph+ ALL, as monotherapy;
• adults with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with rearrangement of platelet-derived growth factor receptor (PDGFR) genes;
• adults with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) with FIP1L1-PDGFRα gene rearrangement.

No effect of Neopax® on the outcome of bone marrow transplantation has been demonstrated.

Neopax® is indicated for:

• treatment of adults with Kit (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST);
• adjuvant treatment of adults who are at significant risk of recurrence of Kit (CD117)-positive malignant GIST after resection; patients with low or very low risk of recurrence should not receive adjuvant therapy;
• treatment of adults with unresectable dermatofibrosarcoma protuberans (DFSP) and adults with recurrent and/or metastatic DFSP not amenable to surgical removal.

In adults and children, the efficacy of Neopax® is based on overall hematologic and cytogenetic response and progression-free survival in CML, on the rate of hematologic and cytogenetic response in Ph+ ALL and MDS/MPD, on the rate of hematologic response in HES/CEL, and on the rate of objective response in adults with unresectable and/or metastatic GIST and DFSP, as well as on recurrence-free survival in adjuvant GIST. Experience with Neopax® in patients with MDS/MPD associated with PDGFR gene rearrangement is very limited (see "Pharmacological properties"). Except for newly diagnosed chronic phase CML, there are no controlled studies demonstrating clinical benefit or increased survival in these diseases.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Active substances that may increase plasma concentration of imatinib

Interaction with substances that inhibit the activity of the CYP3A4 isoenzyme of cytochrome P450 (protease inhibitors such as indinavir, lopinavir/ritonavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; antifungal azoles including ketoconazole, itraconazole, posaconazole, voriconazole, as well as some macrolides such as erythromycin, clarithromycin, and telithromycin) may lead to reduced metabolism and increased plasma concentration of imatinib. A significant increase in the effect of imatinib (mean Cmax and AUC of imatinib increased by 26% and 40%, respectively) was observed in healthy volunteers when administered concomitantly with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution is required when prescribing imatinib with CYP3A4 inhibitors.

Active substances that may decrease plasma concentration of imatinib

Substances that are inducers of CYP3A4 activity (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, fosphenytoin, primidone, or St. John's wort preparations) may significantly reduce the effect of imatinib, potentially increasing the risk of therapeutic failure. Pre-treatment with multiple doses of rifampicin 600 mg followed by a single 400 mg dose of imatinib resulted in a reduction of Cmax and AUC (0 - ∞) by at least 54% and 74%, respectively, compared to values without rifampicin. Similar results were observed in patients with malignant gliomas receiving imatinib while taking enzyme-inducing anticonvulsants (EIACs) such as carbamazepine, oxcarbazepine, and phenytoin. Compared to patients not taking EIACs, plasma AUC values for imatinib decreased by 73%. Concomitant use of rifampicin or other potent CYP3A4 inducers with imatinib should be avoided.

Active substances whose plasma concentrations may be altered by imatinib

Imatinib increases the mean Cmax and AUC of simvastatin (a CYP3A4 substrate) by 2- and 3.5-fold, respectively, indicating inhibition of CYP3A4 by imatinib. Therefore, caution is recommended when co-administering imatinib with CYP3A4 substrates that have a narrow therapeutic window (e.g., cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, dihydroergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel, and quinidine). Imatinib may increase plasma concentrations of other drugs metabolized by CYP3A4 (such as triazole benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, i.e., statins, etc.).

Due to the known increased risk of bleeding associated with imatinib use (e.g., hemorrhage), patients requiring anticoagulant therapy should receive low molecular weight heparins or standard heparin instead of coumarin derivatives such as warfarin.

In vitro, imatinib inhibits the activity of the CYP2D6 isoenzyme of cytochrome P450 at concentrations similar to those affecting CYP3A4 activity. Imatinib at a dose of 400 mg twice daily inhibits CYP2D6-mediated metabolism of metoprolol, increasing Cmax and AUC of metoprolol by approximately 23% (90% CI [1.16–1.30]). Dose adjustment is not necessary when imatinib is co-administered with CYP2D6 substrates; however, caution is recommended when prescribing imatinib with CYP2D6 substrates having a narrow therapeutic window, such as metoprolol. Clinical monitoring should be considered for patients receiving metoprolol.

In vitro, imatinib inhibits O-glucuronidation of paracetamol with a Ki value of 58.5 µmol/L. This inhibition was not observed in vivo after administration of 400 mg imatinib and 1000 mg paracetamol. The effect of higher doses of imatinib and paracetamol has not been studied.

Therefore, caution should be exercised when administering high doses of imatinib and paracetamol concomitantly.

In patients after thyroidectomy receiving levothyroxine, plasma exposure to levothyroxine may be reduced when imatinib is administered concomitantly, which should be taken into account. However, the mechanism of drug interaction remains unknown.

There is clinical experience with concomitant administration of imatinib with chemotherapy in Ph+ ALL patients, but the drug interaction between imatinib and chemotherapeutic agents is not very favorable. The frequency of adverse events associated with imatinib, such as hepatotoxicity, myelosuppression, and others, may increase. Administration of imatinib together with L-asparaginase has been reported to be associated with increased hepatotoxicity. Thus, use of imatinib in combination with other medicinal products requires special caution.

Special precautions for use.

Concomitant use of imatinib with other medicinal products may lead to interactions. Imatinib should be used with caution together with protease inhibitors, azole antifungals, certain macrolides (see section "Interaction with other medicinal products and other forms of interaction"), substrates of CYP3A4 with a narrow therapeutic window (such as cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, dihydroergotamine, fentanyl, alfentanil, terfenadine, bortezomib, docetaxel, quinidine), or warfarin and other coumarin derivatives.

Concomitant administration of imatinib and medicinal products that induce CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital, or St. John's wort preparations) may significantly reduce the effect of imatinib, potentially increasing the risk of therapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers and imatinib should be avoided.

Hypothyroidism

Clinical cases of hypothyroidism have been reported in patients after thyroidectomy who were receiving levothyroxine replacement therapy during imatinib treatment. In such patients, thyroid-stimulating hormone (TSH) levels should be closely monitored.

Hepatotoxicity

Imatinib is primarily metabolized in the liver, and only 13% of the drug is excreted by the kidneys. Patients with impaired liver function (mild, moderate, or severe) should be closely monitored for peripheral blood parameters and liver enzyme levels. Patients with GIST may have liver metastases, which can lead to impaired liver function.

Hepatic injury, including hepatic failure and liver necrosis, has been reported during imatinib therapy. When imatinib was used in combination with high-dose chemotherapy, an increased frequency of serious hepatic reactions was observed. Liver function should be closely monitored when imatinib is used concomitantly with chemotherapeutic agents that cause liver dysfunction (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Fluid retention

Severe fluid retention (pleuritis, edema, pulmonary edema, ascites, superficial edema) has been reported in approximately 2.5% of patients with newly diagnosed CML who received imatinib. Therefore, regular monitoring of the patient's body weight is strongly recommended. The causes of unexpected rapid weight gain should be carefully investigated, and appropriate supportive and therapeutic measures should be taken if necessary. During clinical trials, an increased incidence of such events was observed in elderly patients and in patients with a history of heart disease. Therefore, caution should be exercised when administering imatinib to patients with cardiac dysfunction.

Patients with heart disease

Careful monitoring is required for patients with heart disease, risk factors for heart failure, or a history of renal insufficiency. Patients with symptoms of cardiac or renal failure should be evaluated and treated appropriately.

In patients with hypereosinophilic syndrome (HES), isolated cases of cardiogenic shock/left ventricular dysfunction have been reported at the beginning of imatinib therapy, associated with degranulation of HES cells due to myocardial infiltration by HES cells in a latent form. This condition has been reported to be reversible with administration of systemic steroids, hemodynamic support measures, and temporary discontinuation of imatinib. Cardiac adverse events during imatinib therapy are infrequent; however, a careful benefit-risk assessment should be performed before initiating therapy in the HES/CEL population.

Myelodysplastic/myeloproliferative disorders with PDGFR gene rearrangements and systemic mastocytosis may be associated with high levels of eosinophilia. Therefore, prior to initiating imatinib, cardiology consultation, echocardiography, and serum troponin measurement are recommended in patients with HES/CEL and in patients with MDS/MPD or SM associated with high levels of eosinophilia. In case of any suspicious symptoms at the initiation of imatinib therapy, consideration should be given to cardiology monitoring and prophylactic use of systemic steroids (1–2 mg/kg) for one to two weeks.

Gastrointestinal hemorrhage

During studies in patients with unresectable and/or metastatic GIST, bleeding events were reported both in the gastrointestinal tract and within the tumor. Based on available data, no risk factors (such as tumor size or location, coagulation disorders) were identified that increase the risk of bleeding of any type in patients with GIST. Since increased vascularization and increased bleeding tendency are components of the pathogenesis and clinical course of GIST, standard methods and procedures for monitoring and treating bleeding should be applied in all patients.

Additionally, post-marketing surveillance reports have described gastric antral vascular ectasias as a rare cause of gastrointestinal bleeding in patients with CML, ALL, and other conditions. If necessary, discontinuation of imatinib may be considered.

Tumor lysis syndrome (TLS)

Due to the potential for TLS, correction of clinically significant dehydration and treatment of elevated uric acid levels are recommended before initiating imatinib.

Reactivation of hepatitis B

Hepatitis B reactivation in patients who are chronic carriers of the virus has occurred after these patients received BCR-ABL tyrosine kinase inhibitors.

In some cases, this led to acute liver failure or fulminant hepatitis requiring liver transplantation or resulting in fatal outcomes. Patients should be tested for HBV infection prior to starting treatment.

Patients with positive serological tests for hepatitis B (including those with active disease) and patients with confirmed HBV infection should be referred for consultation with infectious disease specialists and hepatologists experienced in managing hepatitis B before initiating treatment. Patients who are hepatitis B virus carriers and require imatinib therapy should be closely monitored for signs of active hepatitis B infection during treatment and for several months after treatment completion.

Photosensitivity

Exposure to direct sunlight should be avoided or minimized due to the risk of photosensitivity associated with imatinib use. Patients should be advised to wear protective clothing and use sunscreen with a high sun protection factor (SPF).

Thrombotic microangiopathy

BCR-ABL tyrosine kinase inhibitors (TKIs) have been associated with thrombotic microangiopathy (TMA), including isolated reports with Neopax (see section "Adverse reactions"). If a patient receiving Neopax experiences laboratory or clinical findings suggestive of TMA, treatment should be discontinued and a thorough evaluation for TMA, including ADAMTS13 activity and anti-ADAMTS13 antibody testing, should be completed. If anti-ADAMTS13 antibodies are elevated in combination with low ADAMTS13 activity, Neopax treatment should not be continued.

Laboratory tests

Complete blood counts should be performed regularly during imatinib therapy. Treatment of CML patients with imatinib is associated with the development of neutropenia or thrombocytopenia. However, the occurrence of these cytopenias is likely related to the disease stage at which treatment is initiated and was more frequent in patients with acute phase CML or blast crisis compared to patients with chronic phase CML. Treatment with imatinib may be interrupted or the dose reduced.

Liver function (transaminase, bilirubin, and alkaline phosphatase levels) should be monitored regularly in patients receiving imatinib.

Plasma imatinib concentrations are generally higher in patients with impaired renal function compared to patients with normal renal function. This is likely due to elevated plasma levels of alpha-1-acid glycoprotein (AAG), a protein that binds imatinib, in these patients. Treatment of patients with impaired renal function should be initiated with the lowest recommended starting dose. Patients with severe renal impairment require cautious treatment. The dose may be reduced in case of intolerance.

Long-term use of imatinib may be associated with clinically significant deterioration in renal function. Renal function should be assessed before starting imatinib therapy and monitored during treatment, with particular attention to patients who have risk factors for renal dysfunction. If renal impairment occurs, treatment should be administered according to standard guidelines.

Pediatric population

Cases of growth retardation have been reported in children receiving imatinib. In an observational study of pediatric CML patients, statistically significant decreases (but of uncertain clinical significance) in mean standard deviation scores for height were observed after 12 and 24 months of treatment in two small subgroups, regardless of pubertal status and sex. Similar findings were observed in an observational study across all pediatric groups. Close monitoring of growth is recommended in children receiving imatinib therapy (see section "Adverse reactions").

Neopax® contains lactose. Patients with rare hereditary conditions of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception during treatment and for at least 15 days after discontinuation of Neopax®.

Pregnancy

Data on the use of imatinib in pregnant women are limited. Post-marketing reports have described spontaneous abortions and congenital anomalies in infants of women who took imatinib. However, animal studies have shown reproductive toxicity and potential fetal risk. Imatinib should not be used during pregnancy unless clearly necessary. If imatinib is used during pregnancy, the patient should be informed of the potential risk to the fetus.

Breastfeeding

Information on imatinib concentrations in breast milk is limited. Studies involving two breastfeeding women showed that imatinib and its active metabolite can be excreted into breast milk. The milk-to-plasma ratio studied in one patient was 0.5 for imatinib and 0.9 for the metabolite, suggesting a significant amount of metabolite in breast milk. Considering the combined concentrations of imatinib and metabolite and the maximum daily milk intake by breastfed infants, the total expected exposure was low (~10% of the therapeutic dose). However, due to the unknown consequences of exposure to low doses of imatinib in infants, women taking imatinib and for at least 15 days after discontinuation of Neopax® should not breastfeed.

Fertility

In preclinical studies, no effect on fertility in male or female rats was observed, although effects on reproductive parameters were noted. Studies in patients receiving imatinib and its effects on fertility and gametogenesis have not been conducted. Patients concerned about fertility during imatinib treatment should consult their physician.

Ability to affect reaction speed when driving or operating machinery.

Patients should be warned that during imatinib treatment they may experience adverse effects such as dizziness, blurred vision, or somnolence. Therefore, caution should be exercised when driving or operating machinery.

Administration and Dosage

Treatment should be administered by a physician experienced in the management of patients with hematologic malignancies and malignant sarcomas, depending on the indication.

Tablets of 400 mg (non-divisible) are available for doses of 400 mg and higher (see dosage recommendations below).

Tablets of 100 mg (scored, divisible) are available for doses other than 400 mg and 800 mg (see dosage recommendations below).

The prescribed dose should be taken orally with food and a large glass of water to minimize gastrointestinal disturbances. Doses of 400 mg and 600 mg should be taken once daily, whereas the 800 mg dose should be divided into two daily doses of 400 mg each, taken in the morning and evening.

For patients unable to swallow film-coated tablets, these tablets may be dissolved in a glass of water or apple juice. The required number of tablets should be dissolved in an appropriate volume of liquid (approximately 50 mL for a 100 mg tablet and 200 mL for a 400 mg tablet). The resulting suspension should be taken immediately after complete dissolution of the tablet(s).

Dosage for adult patients with CML

The recommended dose of Neopax® for adult patients with chronic phase CML is 400 mg/day. Chronic phase CML is defined by the presence of the following criteria: <15% blasts in blood and bone marrow, basophils in peripheral blood <20%, platelets >100 * 10⁹/L.

For adult patients in the accelerated phase, the recommended dose of Neopax® is 600 mg/day.

Accelerated phase is defined by the presence of any of the following: blasts ≥15% but <30% in blood or bone marrow, blasts and promyelocytes ≥30% in blood or bone marrow (provided blasts <30%), basophils in peripheral blood ≥20%, platelets <100 * 10⁹/L or >100 * 10⁹/L not related to therapy.

The recommended dose of Neopax® in blast crisis is 600 mg/day. Blast crisis is defined by the presence of ≥30% blasts in blood or bone marrow or extramedullary disease, excluding hepatosplenomegaly.

Duration of treatment. In clinical studies, treatment with Neopax® was continued until evidence of disease progression. The effect of discontinuing treatment after achieving a complete cytogenetic response has not been studied.

Dose escalation from 400 mg to 600 mg or 800 mg may be considered for patients in chronic phase, and from 600 mg to a maximum of 800 mg (administered as 400 mg twice daily) for patients in accelerated phase or blast crisis, in the absence of severe adverse reactions and severe non-leukemia-related neutropenia or thrombocytopenia, under the following circumstances: disease progression (at any time); failure to achieve a satisfactory hematologic response after at least 3 months of therapy; loss of previously achieved cytogenetic response after 12 months of therapy; or loss of previously achieved hematologic or cytogenetic response.

Patients should be closely monitored after dose escalation, as the frequency of adverse effects increases with higher doses.

Dosage for pediatric patients with CML

Dosing for children or adolescents should be based on body surface area (mg/m²). A dose of 340 mg/m²/day is recommended for children or adolescents with chronic phase CML or accelerated phase (maximum total daily dose should not exceed 800 mg). The drug may be administered once daily or the daily dose may be divided into two doses, morning and evening. Recommended doses are currently based on experience from a limited number of pediatric patients. Experience with treatment in children under 2 years of age is lacking.

Dose escalation from 340 mg/m² to 570 mg/m²/day (maximum total daily dose should not exceed 800 mg) may be considered for children or adolescents in the absence of severe adverse reactions and severe non-leukemia-related neutropenia or thrombocytopenia, under the following circumstances: disease progression (at any time); failure to achieve a satisfactory hematologic response after at least 3 months of therapy; loss of previously achieved cytogenetic response after 12 months of therapy; or loss of previously achieved hematologic or cytogenetic response.

Patients should be closely monitored after dose escalation, as the frequency of adverse effects increases with higher doses.

Dosage for Ph-positive (Ph+) ALL in adults

The recommended dose of Neopax® for adult patients with Ph+ ALL is 600 mg/day.

Hematologists should supervise therapy throughout all stages of care for this disease.

Based on available data, imatinib has demonstrated efficacy and safety at a dose of 600 mg/day when administered in combination with chemotherapy during induction, consolidation, and maintenance phases for adult patients with newly diagnosed Ph+ ALL. The duration of Neopax® therapy may vary according to the chosen treatment regimen, but longer imatinib treatment has generally shown better therapeutic outcomes.

For adult patients with relapsed or refractory Ph+ ALL, a daily dose of 600 mg as monotherapy is safe and effective and may be continued until evidence of disease progression.

Dosage for Ph-positive (Ph+) ALL in children

Dosing for children should be based on body surface area (mg/m²). The recommended daily dose for children with Ph+ ALL is 340 mg/m² (maximum daily dose should not exceed 600 mg).

Dosage for MDS/MPN

The recommended dose of Neopax® for adult patients with MDS/MPN is 400 mg/day.

In the only clinical study conducted to date, imatinib treatment was continued until evidence of disease progression. At the time of analysis, the median duration of treatment was 47 months (range: 24 days to 60 months).

Dosage for GIST and/or HES

The recommended dose of Neopax® for patients with GIST/HES is 100 mg/day.

Dose escalation from 100 mg/day to 400 mg/day may be considered in the absence of adverse reactions or inadequate treatment efficacy.

Treatment should be continued as long as therapeutic benefit is observed.

Dosage for patients with Kit (CD117)-positive unresectable and/or metastatic malignant GIST and for adjuvant therapy in adult patients at high risk of recurrence of Kit (CD117)-positive malignant GIST after resection

The recommended dose of Neopax® for patients with unresectable and/or metastatic malignant GIST is 400 mg/day.

There is limited data on dose escalation from 400 mg/day to 600 mg or 800 mg/day in patients with disease progression on lower doses.

In clinical trials involving patients with GIST, imatinib treatment was continued until disease progression. At the time of analysis, the median duration of treatment was 7 months (range: 7 days to 13 months). The effect of discontinuing treatment after achieving a response has not been studied.

The recommended dose of Neopax® for adjuvant therapy in adult patients following resection of GIST is 400 mg/day. The optimal duration of treatment has not yet been established. The treatment duration in the clinical trial for this indication was 36 months.

Dosage for unresectable dermatofibrosarcoma protuberans (DFSP)

The recommended dose of Neopax® for patients with DFSP is 800 mg/day.

Dose adjustments for adverse reactions

Non-hematologic adverse reactions

In the event of severe non-hematologic adverse reactions during Neopax® treatment, therapy should be withheld until improvement. Treatment may then be resumed as necessary, depending on the severity of the prior event.

If bilirubin levels increase to more than 3 times the upper limit of normal (ULN) or liver transaminases increase to more than 5 times ULN, imatinib therapy should be withheld until bilirubin levels return to less than 1.5 times ULN and liver transaminase levels return to less than 2.5 times ULN. Imatinib therapy may then be resumed at a reduced daily dose. For adults, the dose should be reduced from 400 to 300 mg, from 600 to 400 mg, or from 800 to 600 mg/day. For children or adolescents, the dose should be reduced from 340 to 260 mg/m²/day.

Hematologic adverse reactions

Dose reduction or discontinuation is recommended in the event of severe neutropenia or thrombocytopenia, as outlined in Table 8.

Table 8

Dose modification for neutropenia and thrombocytopenia

Special patient groups

Pediatric use. There is no experience with the use of Neopax® in children with CML under 2 years of age, or in children with Ph+ ALL under 1 year of age.

Experience in children with MDS/MPN, DFSP, GIST, and GES/HEL is very limited.

The safety and efficacy of imatinib in children (under 18 years of age) with MDS/MPN, DFSP, GIST, and GES/HEL have not been established in clinical trials. Published data are available, but it is not possible to formulate dosage recommendations.

Hepatic impairment. Imatinib is primarily metabolized by the liver. Patients with mild, moderate, or severe hepatic dysfunction should receive the minimum recommended dose of 400 mg once daily. The dose may be reduced if not well tolerated.

Table 9

Classification of hepatic dysfunction

ULN – upper limit of normal.

AST – aspartate aminotransferase.

Renal impairment. In patients with renal dysfunction or those undergoing dialysis, the initial dose should be set at the minimum recommended dose level – 400 mg per day. However, therapy in these patients should be conducted with caution. If the drug is not well tolerated, the dose may be reduced. If the drug is well tolerated but insufficient efficacy is observed, the dose may be increased.

Elderly patients. The pharmacokinetics of imatinib in elderly individuals has not been specifically studied. Among adult patients in clinical trials, including more than 20% of patients aged 65 years and older, no significant age-related differences in pharmacokinetics were observed. There are no specific dosing recommendations for elderly patients.

Children.

There is no experience with the use of Neopax® in children with CML under 2 years of age, and in children with Ph+ ALL under 1 year of age.

Experience with use in children with MDS/MPN, DFSP, GIST, and GES/RCC is very limited.

The safety and efficacy of imatinib in children (under 18 years of age) with MDS/MPN, DFSP, GIST, and GES/RCC have not been established in clinical trials. Published data are available, but dosing recommendations cannot be developed.

Overdose.

Experience with doses higher than the recommended therapeutic dose is limited. Individual reports of imatinib overdose have been reported spontaneously or published. In case of overdose, the patient should be monitored and appropriate symptomatic treatment should be administered. Overall, outcomes of such cases have generally been reported as "improvement" or "recovery."

Adults

1200–1600 mg (duration from 1 to 10 days): nausea, vomiting, diarrhea, rash, erythema, edema, swelling, fatigue, muscle cramps, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

1800–3200 mg (3200 mg daily for 6 days): weakness, myalgia, elevated creatine phosphokinase, elevated bilirubin, gastrointestinal pain.

6400 mg (single dose): one case in which the patient experienced nausea, vomiting, abdominal pain, elevated body temperature, facial swelling, decreased neutrophil count, and elevated transaminase levels.

8 to 10 g (single dose): vomiting and gastrointestinal tract pain were recorded.

Children

In one 3-year-old boy, a single 400 mg dose resulted in vomiting, diarrhea, and anorexia. In another 3-year-old boy, a single 980 mg dose resulted in decreased leukocyte count and diarrhea.

In case of overdose, the patient should be monitored and appropriate supportive treatment should be administered.

Adverse reactions.

Adverse reactions reported more frequently than in isolated cases are listed below by system organ classes and by frequency. Frequency categories are defined according to the following scale: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Within each frequency category, adverse reactions are listed in order of decreasing severity.

Table 10

Adverse reactions in clinical studies

* These types of reactions were mainly observed during the post-marketing period of imatinib use. They include spontaneous case reports as well as serious adverse effects observed during long-term studies, expanded access programs, clinical pharmacology studies, and investigational use outside approved indications. Because these reactions occurred in populations of undefined size, their frequency cannot always be reliably determined or a causal relationship to imatinib use established.

1 Pneumonia was most frequently reported in patients with transformed CML and patients with gastrointestinal stromal tumors (GIST).

2 Headache was most frequently reported in patients with gastrointestinal stromal tumors (GIST).

3 Based on patient-year calculations, cardiac function disorders, including congestive heart failure, were more frequently observed in patients with transformed CML than in patients with chronic-phase CML.

4 Flushing was most frequently observed in patients with gastrointestinal stromal tumors (GIST), while hemorrhages (hematomas, hemorrhagic events) were most frequently observed in patients with gastrointestinal stromal tumors (GIST) and transformed CML (CML-AP and CML-BC).

5 Pleural effusion was reported more frequently in patients with gastrointestinal stromal tumors (GIST) and patients with transformed CML (CML-AP and CML-BC) than in patients with chronic-phase CML.

6+7 Abdominal pain and gastrointestinal hemorrhages were most frequent in patients with gastrointestinal stromal tumors (GIST).

8 There have been reports of some fatal cases of liver failure and hepatic necrosis.

9 Musculoskeletal pain during or after discontinuation of imatinib treatment was observed during post-marketing surveillance.

10 Musculoskeletal pain and similar reactions were more frequently observed in patients with CML than in patients with gastrointestinal stromal tumors (GIST).

11 Fatal cases have been reported in patients with advanced disease stages, severe infections, severe neutropenia, and other serious comorbid conditions.

12 Including nodular erythema.

Laboratory parameter changes

Hematology

In CML, cytopenias, particularly neutropenia and thrombocytopenia, were consistently observed across all studies, with a presumed higher frequency at doses ≥750 mg (Phase I studies). However, the occurrence of cytopenia also clearly depends on the disease stage. The frequency of Grade 3 and 4 neutropenia (absolute neutrophil count <1.0 × 10⁹/L) and thrombocytopenia (platelet count <50 × 10⁹/L) was approximately 4 to 6 times higher in blast crisis and acceleration phases (59–64% and 44–63% for neutropenia and thrombocytopenia, respectively) compared to patients with newly diagnosed chronic-phase CML (16.7% for neutropenia and 8.9% for thrombocytopenia). In newly diagnosed chronic-phase CML, Grade 4 neutropenia (absolute neutrophil count <0.5 × 10⁹/L) and thrombocytopenia (platelet count <10 × 10⁹/L) were observed in 3.6% and <1% of patients, respectively. The average duration of neutropenic and thrombocytopenic episodes was typically 2–3 weeks and 3–4 weeks, respectively. These reactions can usually be managed by dose reduction or temporary interruption of imatinib therapy, although permanent discontinuation is required only in rare cases. In children with CML, the most common toxicities were Grade 3 or 4 cytopenias, including neutropenia, thrombocytopenia, and anemia. These predominantly occurred during the first few months of therapy.

In the course of studies in patients with unresectable and/or metastatic GIST, Grade 3 and 4 anemia was recorded in 5.4% and 0.7% of patients, respectively, which may be related to gastrointestinal or tumor-related hemorrhages, at least in some of these patients. Grade 3 and 4 neutropenia was recorded in 7.5% and 2.7% of patients, respectively, and Grade 3 thrombocytopenia in 0.7% of patients. Grade 4 thrombocytopenia was not observed in any patient. Decreases in leukocyte and neutrophil counts occurred predominantly during the first six weeks of therapy, with relatively stable values thereafter.

Biochemistry

Significant elevations in transaminase levels (<5%) or bilirubin (<1%) were observed in CML patients and were usually managed by dose reduction or therapy interruption (the average duration of such episodes was approximately one week). Treatment was permanently discontinued due to abnormal liver laboratory parameters in less than 1% of CML patients. In GIST patients (Study B2222), Grade 3 and 4 elevations in ALT (alanine aminotransferase) occurred in 6.8% and in AST (aspartate aminotransferase) in 4.8%. Bilirubin elevations were observed in less than 3% of cases.

Cases of cytolytic and cholestatic hepatitis, as well as liver failure, sometimes with fatal outcomes, have been reported, including in one patient who used high-dose paracetamol.

Description of selected adverse reactions

Hepatitis B reactivation

Hepatitis B reactivation has been reported in patients receiving BCR-ABL tyrosine kinase inhibitors (TKIs). In some cases, this led to acute liver failure or fulminant hepatitis, requiring liver transplantation or resulting in death.

Reporting suspected adverse reactions

Reporting adverse reactions after drug registration is important. It enables ongoing 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: https://aisf.dec.gov.ua.

In patients with advanced stages of malignancies, numerous comorbid conditions may be present, complicating the establishment of a causal relationship for adverse reactions due to the wide variety of symptoms associated with the underlying disease, its progression, and concomitant use of multiple medicinal products.

In clinical studies of CML, discontinuation of the medicinal product due to related adverse reactions occurred in 2.4% of patients with newly diagnosed disease, 4% of patients in late chronic phase after prior interferon therapy, 4% of patients in the acceleration phase after prior interferon therapy, and 5% of patients in blast crisis after prior interferon therapy. In GIST, the investigational drug was discontinued due to adverse reactions in 4% of patients.

Adverse reactions were similar across all indications, except for two. In CML patients, a higher frequency of myelosuppression was observed compared to GIST patients, likely related to the underlying disease. In the study of patients with unresectable and/or metastatic GIST, 7 (5%) patients experienced gastrointestinal hemorrhages Grade 3/4 according to toxicity criteria (in 3 patients), intratumoral hemorrhages (in 3 patients), or both (in 1 patient). Gastrointestinal tumor locations could be the source of gastrointestinal bleeding. Gastrointestinal and tumor hemorrhages can be life-threatening and sometimes fatal. The most common (≥10%) adverse reactions associated with drug intake in both cases were mild nausea, vomiting, diarrhea, abdominal pain, fatigue, myalgia, muscle cramps, and rash. Superficial edema was frequently observed in all studies and was mostly described as periorbital edema or lower limb edema. However, these edemas were rarely severe and were managed with diuretics, other supportive measures, or dose reduction of imatinib.

When imatinib was combined with high-dose chemotherapy in Ph+ ALL patients, transient hepatic toxicity was observed, manifested as elevated transaminase levels and hyperbilirubinemia. Given the limited safety data, the adverse reactions reported so far in children are consistent with the safety profile in adult Ph+ ALL patients. The safety profile in pediatric Ph+ ALL patients is very limited, but no new safety concerns have been identified.

Various adverse reactions such as pleuritis, ascites, pulmonary edema, and rapid weight gain with or without superficial edema may generally be classified as fluid retention. Such reactions can usually be managed with diuretics, temporary interruption of imatinib, and other appropriate supportive measures. However, some of these reactions may be serious or life-threatening; some patients with blast crisis and complex clinical histories involving pleural effusion, congestive heart failure, and renal failure have died. No specific safety conclusions have been made from pediatric clinical trials.

Shelf life. 3 years.

Storage conditions.

This medicinal product does not require special storage conditions.

Keep out of reach and sight of children.

Packaging.

For 100 mg dosage:

10 tablets in a blister; 1, 6, or 12 blisters in a cardboard box.

For 400 mg dosage:

10 tablets in a blister; 1, 3, or 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's location and address of business operations.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia.

Manufacturer. KRKA-PHARMA d.o.o., Croatia.

Manufacturer's location and address of business operations.

V. Holjevca 20/E, 10450 Jastrebarsko, Croatia.