Glivec

Glivec

imatinib

Manufacturer:

Novartis

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Imatinib (as mesilate β crystals).
Description
Glivec also contains the following excipients: Microcrystalline cellulose, crospovidone, hypromellose, magnesium stearate and anhydrous colloidal silica. The coating contains red iron oxide (E172) and yellow iron oxide (E172).
Action
Pharmacotherapeutic Group: Protein-tyrosine kinase inhibitor.
Pharmacology: Pharmacodynamics: Imatinib is a protein-tyrosine kinase inhibitor which potently inhibits the breakpoint cluster region-Abelson (Bcr-Abl) tyrosine kinase at the in vitro, cellular, in vivo levels. The compound selectively inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines, as well as fresh leukemic cells from Philadelphia chromosome-positive chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL) patients. In colony transformation assays using ex vivo peripheral blood and bone marrow samples, imatinib shows selective inhibition of Bcr-Abl positive colonies from CML patients.
In vivo, the compound shows antitumour activity as a single agent in animal models using Bcr-Abl positive tumour cells.
Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem-cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumour (GIST) cells, which express an activating kit mutation. Constitutive activation of the PDGFR or the Abl protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutive production of PDGF have been implicated in the pathogenesis of myelodysplastic/myeloproliferative diseases (MDS/MPD), hypereosinophilic syndrome/chronic eosinophilic leukaemia (HES/CEL) and dermatofibrosarcoma protuberans (DFSP). In addition, constitutive activation of c-Kit or the platelet-derived growth factor receptor (PDGFR) has been implicated in the pathogenesis of systemic mastocytosis (SM). Imatinib inhibits signalling and proliferation of cells driven by dysregulated PDGFR, Kit and Abl kinase activity.
Clinical Studies in CML: The effectiveness of Glivec is based on overall haematological and cytogenetic response rates and progression-free survival. Except in newly diagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit eg, improvement in disease-related symptoms or increased survival.
Three large, international, open-label, noncontrolled phase II studies were conducted in patients with Philadelphia chromosome positive (Ph+) CML in advanced, blast or accelerated phase disease, other Ph+ leukaemias or with CML in the chronic phase but failing prior interferon-α (IFN) therapy. One large, open-label, multicenter, international randomized phase III study has been conducted in patients with newly diagnosed Ph+ CML. In addition, children have been treated in 2 phase I studies and 1 open-label, multicenter, single-arm phase II trial.
In all clinical studies, 38-40% of patients were ≥60 years and 10-12% of patients were ≥70 years.
Chronic Phase, Newly Diagnosed: This phase III study compared treatment with either single-agent Glivec or a combination of interferon-α (IFN) plus cytarabine (Ara-C). Patients showing lack of response [lack of complete haematological response (CHR) at 6 months, increasing white blood cells (WBC), no major cytogenetic response (MCyR) at 24 months], loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment arm. In the Glivec arm, patients were treated with 400 mg daily. In the IFN arm, patients were treated with a target dose of IFN 5 MIU/m2/day SC in combination with SC Ara-C 20 mg/m2/day for 10 days/month.
A total of 1106 patients have been randomized from 177 centers in 16 countries, 553 to each arm. Baseline characteristics were well balanced between the 2 arms. Median age was 51 years (range 18-70 years), with 21.9% of patients ≥60 years. There were 59% males and 41% females; 89.9% Caucasians and 4.7% Blacks. At the cut-off for this analysis (5 years after the last patient had been recruited), the median duration of 1st-line treatment was 60 and 8 months in the Glivec and IFN arm, respectively. The median duration of 2nd-line treatment with Glivec was 45 months. Sixty-nine percent of patients randomized to Glivec are still receiving 1st-line treatment. In these patients, the average dose of Glivec was 382±50 mg. Overall, in patients receiving 1st-line Glivec, the average daily dose delivered was 389±71 mg. As a consequence of a higher rate of both discontinuations and crossovers, only 3% of patients randomized to IFN are still receiving 1st-line treatment. In the IFN arm, withdrawal of consent (14%) was the most frequent reason for discontinuation of 1st-line therapy and the most frequent reason for crossover to the Glivec arm was severe intolerance to treatment (26%) and progression (14%). The primary efficacy endpoint of the study is progression-free survival. Progression was defined as any of the following events: Progression to accelerated phase or blast crisis (AP/BC), death, loss of CHR or MCyR or in patients not achieving a CHR an increasing WBC despite appropriate therapeutic management. Major cytogenetic response, haematological response, molecular response (evaluation of minimal residual disease), time to accelerated phase or blast crisis and survival are main secondary endpoints. Response data are shown in Table 1. (See Table 1.)

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Rates of complete haematological response, major cytogenetic response and complete cytogenetic response (CCyR) on 1st-line treatment were estimated using the Kaplan-Meier approach, for which nonresponses were censored at the date of last examination. Using this approach, the estimated cumulative response rates for 1st-line treatment with Glivec are shown in Table 2. (See Table 2.)

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For analysis of long-term outcomes, patients randomized to receive Glivec were compared with patients randomized to receive IFN. Patients who crossed-over prior to progression were not censored at the time of crossover and events that occurred in these patients following crossover were attributed to the original randomized treatment.
With 5 years follow-up, there were 86 (15.6%) progression events in the Glivec arm: 35 (6.3%) involving progression to AP/BC, 28 (5.1%) loss of MCyR, 14 (2.5%) loss of CHR or increase in WBC and 9 (1.6%) CML unrelated deaths. In contrast, there were 155 (28%) events in the IFN+Ara-C arm of which 128 occurred during 1st-line treatment with IFN+Ara-C.
The estimated rate of progression-free survival at 60 months is 83.2% with 95% CI (79, 87) in the Glivec arm and 64.1% (59, 69) in the control arm (p<0.001). The yearly rates of progression for Glivec were 3.3% in the 1st year after start of study, 7.5% in the 2nd year and 4.8%, 1.5% and 0.9% in the 3rd, 4th and 5th year of study, respectively.
The estimated rate of patients free of progression to accelerated phase or blast crisis at 60 months was significantly higher in the Glivec arm compared to the IFN arm (92.9% versus 86.2%, p<0.001). The annual rate of progression decreased with time on therapy: Yearly rates of disease progression to accelerated phase or blast crisis were 1.5%, 2.8%, 1.6%, 0.9% and 0.6% in the 1st to 5th year, respectively.
A total of 57 (10.3%) and 73 (13.2%) patients died in the Glivec and IFN+Ara-C groups, respectively. At 60 months, the estimated overall survival is 89.4% (86, 92) versus 85.6% (82, 89) in the randomized Glivec and the IFN+Ara-C groups, respectively (p=0.049, log-rank test). This time-to-event endpoint is strongly affected by the high crossover rate from IFN+Ara-C to Glivec. Additionally, a greater number of patients received bone marrow transplant (BMT) after discontinuation of study treatment in the IFN+Ara-C group (n=61, 34 after crossover to Glivec) compared with the Glivec group (n=44, 8 after crossover to IFN). When censoring the 39 deaths that occurred after BMT, the estimated 60-month survival rates were 91.6% versus 90% (p=0.261, log-rank test). Only 23 (4.2%) deaths (before BMT) of the Glivec patients were attributed to CML, compared to 37 (6.7%) of the IFN+Ara-C patients. When only considering these CML-related deaths and censoring any deaths after BMT or due to other reasons, the estimated 60-month survival rates were 95.4% versus 92.2% (p=0.021, log-rank test). The effect of Glivec treatment on survival in chronic phase, newly diagnosed CML has been further examined in a retrospective analysis of the previously reported Glivec data with the primary data from another phase III study using IFN+Ara-C (n=325) in an identical regimen. In this publication, the superiority of Glivec over IFN+Ara-C in overall survival was demonstrated (p<0.001); within 42 months, 47 (8.5%) Glivec patients and 63 (19.4%) IFN+Ara-C patients had died.
The degree of cytogenetic response had a clear effect on long-term outcomes in patients on Glivec. Whereas an estimated 97% of patients with CCyR (PCyR) at 12 months were free of progression to AP/BC at 60 months, only 81% of patients without MCyR at 12 months were free of progression to advanced CML at 60 months (p<0.001 overall, p=0.2 between CCyR and PCyR). Based on the 18-month landmark, the estimates were 99%, 90% and 83%, respectively, now also including a statistically significant difference between CCyR and PCyR (p<0.001).
Molecular monitoring represented important additional prognostic information. For patients with CCyR and reduction in Bcr-Abl transcripts of at least 3 logarithms at 12 months, the probability of remaining progression-free at 60 months was numerically greater when compared to patients who had CCyR but <3 log reduction (95% versus 89%, p=0.068) and significantly greater than that observed for patients who were not in CCyR at 12 months (70%, p<0.001). Considering only progression to AP/BC, the estimated rates without event were 100%, 95% and 88%, respectively (p<0.001 overall, p=0.007 between CCyR with and without MMR). Using the 18-month landmark, the estimated rates without AP/BC at 60 months were 100% for patients with CCyR and MMR, 98% for patients with CCyR but without MMR and only 87% for patients without CCyR (p<0.001 overall, p=0.105 between CCyR with and without MMR).
In this study, dose escalations were allowed from 400-600 mg daily, then from 600-800 mg daily. After 42 months of follow-up, 11 patients who achieved a complete haematological response at 3 months and a major cytogenetic response at 12 months while on a daily dose of 400 mg experienced a confirmed loss (within 4 weeks) of their cytogenetic response. Of these 11 patients, 4 patients escalated up to 800 mg daily, 2 of whom regained a cytogenetic response (1 partial and 1 complete, the latter also achieving a molecular response), while of the 7 patients in whom the dose was not escalated, only 1 regained a complete cytogenetic response. The percentage of some adverse reactions was higher in the 40 patients in whom the dose was increased to 800 mg daily compared to the population of patients before dose increase (n=551). These more frequent adverse reactions included gastrointestinal haemorrhages, conjunctivitis and elevation of transaminases or bilirubin. Other adverse reactions were reported with lower or equal frequency.
Quality of life (QoL) was measured using the validated FACT-BRM instrument. All domains were assessed and reported significantly higher scores in the Glivec arm compared to the IFN arm. QoL data showed that patients maintain their well-being while on treatment with Glivec.
Chronic Phase, Interferon-Failure: Five hundred thirty-two patients were treated at a starting dose of 400 mg. The patients were distributed in 3 main categories: Haematological failure (29%), cytogenetic failure (35%) or intolerance to interferon (36%). Patients had received a median of 14 months of prior IFN therapy at doses ≥25 x 106 IU/week and were all in late chronic phase, with a median time from diagnosis of 32 months. The primary efficacy variable of the study was the rate of major cytogenetic response (complete plus partial response, 0-35% Ph+ metaphases in the bone marrow).
In this study, 65% of the patients achieved a major cytogenetic response which was complete in 53% of patients (see Table 2). A complete haematological response was achieved in 95% of patients.
Accelerated Phase: Two hundred thirty-five patients with accelerated phase disease were enrolled. The first 77 patients were started at 400 mg, the protocol was subsequently amended to allow higher dosing and the remaining 158 patients were started at 600 mg.
The primary efficacy variable was the rate of haematological response, reported as either complete haematological response, no evidence of leukaemia (ie, clearance of blasts from the marrow and the blood, but without a full peripheral blood recovery as for complete responses) or return to chronic phase CML. A confirmed haematological response was achieved in 71.5% of patients (see Table 3). Importantly, 27.7% of patients also achieved a major cytogenetic response, which was complete in 20.4% of patients. For the patients treated at 600 mg, the current estimates for median progression-free survival and overall survival were 22.9 and 42.5 months, respectively. In a multivariate analysis, a dose of 600 mg was associated with an improved time to progression, independent of platelet count, blood blasts and haemoglobin ≥10 g/L.
Myeloid Blast Crisis: Two hundred sixty patients with myeloid blast crisis were enrolled. Ninety five (37%) had received prior chemotherapy for treatment of either accelerated phase or blast crisis ("pre-treated patients"), whereas 165 (63%) had not ("untreated patients"). The first 37 patients were started at 400 mg, the protocol was subsequently amended to allow higher dosing and the remaining 223 patients were started at 600 mg.
The primary efficacy variable was the rate of haematological response, reported as either complete haematological response, no evidence of leukaemia or return to chronic phase CML, using the same criteria as for the study in accelerated phase. In this study, 31% of patients achieved a haematological response (36% in previously untreated patients and 22% in previously treated patients). The rate of response was also higher in the patients treated at 600 mg (33%) as compared to the patients treated at 400 mg (16%, p=0.022). The current estimate of the median survival of the previously untreated and treated patients was 7.7 and 4.7 months, respectively.

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Paediatric Patients: A total of 51 paediatric patients with newly diagnosed and untreated CML in chronic phase have been enrolled in an open-label, multicentre, single arm phase II trial. Patients were treated with Glivec 340 mg/m2/day, with no interruptions in the absence of dose-limiting toxicity. Glivec treatment induced a rapid response in newly diagnosed paediatric CML patients with a CHR of 78% after 8 weeks of therapy. The high rate of CHR was accompanied by the development of a complete cytogenetic response (CcyR) of 65% which is comparable to the results observed in adults. Additionally, partial cytogenetic response (PcyR) was observed in 16% for a McyR of 81%. The majority of patients who achieved a CcyR developed the CCyR between months 3 and 10 with a median time to response based on the Kaplan-Meier estimate of 5.6 months.
A total of 31 paediatric patients with either chronic phase CML (n=15) or CML in blast crisis or Ph+ acute leukaemias (n=16) have been enrolled in a dose-escalation phase I trial. This was a population of heavily pre-treated patients, as 45% had received prior BMT and 68% a prior multi-agent chemotherapy. Patients were treated at doses of Glivec 260 mg/m2/day (n=6), 340 mg/m2/day (n=11), 440 mg/m2/day (n=8) and 570 mg/m2/day (n=6). Out of 13 patients with CML and cytogenetic data available, 7 (54%) and 4 (31%) achieved a complete and partial cytogenetic response, respectively, for a rate of MCyR of 85%.
Clinical Studies in Ph+ ALL: A total of 758 Ph+ ALL patients with either newly diagnosed or relapsed/refractory disease were enrolled in 10 clinical studies, 9 of which were uncontrolled and 1 randomized.
Newly Diagnosed Ph+ ALL: In a controlled study (ADE10) of imatinib versus chemotherapy induction in 55 newly diagnosed patients ≥55 years, imatinib used as a single agent, induced a significantly higher rate of complete haematological response than chemotherapy (96.3% versus 50%; p=0.0001). When salvage therapy with imatinib was administered in patients who did not respond or who responded poorly to chemotherapy, it resulted in 9 patients (81.8%) out of 11, achieving a complete haematological response. This clinical effect was associated with a higher reduction in Bcr-Abl transcripts in the imatinib-treated patients than in the chemotherapy arm after 2 weeks of therapy (p=0.02). All patients received imatinib and consolidation chemotherapy after induction and the levels of Bcr-Abl transcripts were identical in the 2 arms at 8 weeks. As expected on the basis of the study design, no difference was observed in remission duration, disease-free survival or overall survival, although patients with complete molecular response and remaining in minimal residual disease had a better outcome in terms of both remission duration (p=0.01) and disease-free survival (p=0.02).
The results observed in a population of 211 newly diagnosed Ph+ ALL patients in 4 uncontrolled clinical studies (AAU02, ADE04, AJP01 and AUS01) are consistent with the results described previously, as reported in Table 4 (see Table 4). Imatinib, in combination with chemotherapy induction, resulted in a complete haematological response rate of 93% (147 out of 158 evaluable patients) and in major cytogenetic response rate of 90% (19 out of 21 evaluable patients). The complete molecular response rate was 48% (49 out of 102 evaluable patients).
Similarly, in 2 uncontrolled clinical studies (AFR09 and AIT04) in which 49 newly diagnosed Ph+ ALL patients ≥55 years were given imatinib combined with steroids with or without chemotherapy, there was a complete haematological response rate of 89% in the overall population and a complete molecular response rate of 26% in 39 evaluable patients. Disease-free survival (DFS) and overall survival (OS) constantly exceeded 1 year and were superior to historical control (DFS p<0.001; OS p<0.01) in 3 studies (AJP01, AUS01 and AFR09). (See Table 4.)

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Relapsed/Refractory Ph+ ALL: When imatinib was used as a single agent in patients with relapsed/refractory Ph+ ALL, it resulted, in the 66 out of 429 patients evaluable for response, in a haematological response rate of 33% (12% complete) and a major cytogenetic response rate of 23%. Of note, out of the 429 patients, 353 were treated in an expanded access program without primary response data collected. The median time to progression in the overall population of 429 patients with relapsed/refractory Ph+ ALL ranged from 1.9-3.1 months and median overall survival in the 409 evaluable patients ranged from 5-9 months. In 14 patients, imatinib in combination with induction chemotherapy, resulted in a complete haematological response rate of 92% in 12 evaluable patients and a major cytogenetic response rate of 100% in 8 evaluable patients. Molecular response was assessed in 4 patients and 2 responded completely.
A population of 146 relapsed or refractory patients ≥55 years received imatinib as monotherapy and were analyzed separately because of the lack of curative treatment. A total of 14 out of 146 patients were treated with imatinib 600 mg daily and were evaluable for response; complete haematological response was observed in 5 patients (35%) and major cytogenetic response in 7 patients (50%). Of note, 4 patients who were treated with a lower dose of imatinib (400 mg daily) did not respond, suggesting that this dose is insufficient. In the overall population of 146 patients, median disease-free survival ranged from 2.8-3.1 months and median overall survival from 7.4-8.9 months.
Clinical Studies in MDS/MPD: One open-label, multicentre, phase II clinical trial (study B2225) was conducted testing Glivec in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD out of a total of 185 patients treated, 45 of whom had haematological diseases and 140 a variety of solid tumours. These patients were treated with Glivec 400 mg daily. The ages of the enrolled patients ranged from 20-86 years. A further 24 patients with MDS/MPD aged 2-79 years were reported in 12 published case reports and a clinical study. These patients also received Glivec at a dose of 400 mg daily with the exception of 3 patients who received lower doses. Of the total population of 31 patients treated for MDS/MPD, 14 (45%) achieved a complete haematological response and 9 (29%) a complete cytogenetic response (39% including major and partial responses). Of note, the malignancy carried a translocation, usually involving the chromosome t5q33 or t4q12, resulting in a PDGFR gene rearrangement in 14 evaluable patients. All of these responded haematologically (12 completely). Cytogenetic response was evaluated in 11 out of 14 patients, all of whom responded (9 patients completely). Only 2 (13%) out of the 16 patients without a translocation associated with PDGFR gene rearrangement achieved a complete haematological response and 1 (6%) achieved a major cytogenetic response. A further patient with PDGFR gene rearrangement in molecular relapse after BMT responded molecularly. Median duration of therapy was 12.9 months (0.8-26.7) in the 7 patients treated within study B2225 and ranged between 1 week and >18 months in responding patients in the published literature. Results are provided in Table 5. (See Table 5.)

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Clinical Studies in SM: One open-label, multicentre, phase II clinical trial (study B2225) was conducted testing Glivec in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 5 patients with SM out of a total of 185 patients treated, 45 of whom had haematological diseases and 140 a variety of solid tumours. The SM patients were treated with Glivec 100-400 mg daily. The ages of these patients ranged from 49-74 years. A further 25 patients with SM 26-85 years were reported in 10 published case reports and case series. These patients also received Glivec at doses of 100-400 mg daily. Of the total population of 30 patients treated for SM, 10 (33%) achieved a complete haematological response and 9 (30%) a partial haematological response (63% overall response rate). Cytogenetic abnormalities were evaluated in 21 of the 30 patients treated in the published reports and in the study B2225. Eight out of these 21 patients had FIP1L1-PDGFR-α fusion kinase. Patients with this cytogenetic abnormality are most likely to be males and to have eosinophilia associated with their systemic mast cell disease. Two patients showed a Kit mutation in the juxtamembrane region (one Phe522Cys and one K509I). Sixteen patients had unknown or no detected cytogenetic abnormality. Four patients showed a D816V mutation (the 1 responder had concomitant CML and SM). The majority of patients reported in the reviewed literature with D816V c-Kit mutation are not considered sensitive to Glivec. Median duration of therapy was 13 months (range 1.4-22.3 months) in the 5 patients treated within study B2225 and ranged between 1 month and >30 months in responding patients in the published literature. Results are provided in Table 6. (See Table 6.)

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Clinical Studies in HES/CEL: One open-label, multicentre, phase II clinical trial (study B2225) was conducted testing Glivec in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. In this study, 14 patients with HES/CEL out of a total of 185 patients (45 of whom had haematological diseases and 140 a variety of solid tumours) were treated with 100-1000 mg of Glivec daily. The ages of these patients ranged from 16-64 years. A further 162 patients with HES/CEL 11-78 years were reported in 35 published case reports and case series. These patients received Glivec at doses of 75-800 mg daily. Of the total population of 176 patients treated for HES/CEL, 107 (61%) achieved a complete haematological response and 16 (9%) a partial haematological response (70% overall response rate). Cytogenetic abnormalities were evaluated in 117 of the 176 patients treated in the published reports and in the study B2225. Out of these 117 patients, 61 were positive for FIP1L1-PDGFR-α fusion kinase. All these FIP1L1-PDGFR-α fusion kinase-positive patients achieved a complete haematological response. The FIP1L1-PDGFR-α fusion kinase was either negative or unknown in 115 patients, of which 62 (54%) achieved either a complete (n=46) or partial (n=16) haematological response. Results are provided in Table 7. (See Table 7.)

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Additionally, improvements in symptomatology and other organ dysfunction abnormalities were reported by the investigators in the case reports. Improvements were reported in cardiac, nervous, skin/subcutaneous tissue, respiratory/thoracic/mediastinal, musculoskeletal/connective tissue/vascular and gastrointestinal organ systems.
Clinical Studies in Unresectable or Metastatic GIST: Two open-label, randomized, multinational phase III studies (SWOG, EORTC) were conducted in patients with unresectable or metastatic malignant GIST. The design of these 2 studies were similar allowing a predefined combined analysis of safety and efficacy. A total 1640 patients were enrolled into the 2 studies and randomized 1:1 to receive either 400 or 800 mg orally once daily continously until disease progression or unacceptable toxicity. Patients in the 400 mg once-daily treatment group who experienced disease progression were permitted to crossover to receive treatment with 800 mg once daily. The studies were designed to compare response rates, progression-free survival and overall survival between the dose groups. Median age at patient entry was 60 (range 17-94, 25th-75th age percentile 50-69). Males comprised 58% of the patients enrolled. All patients had a pathologic diagnosis of CD117 positive unresectable and/or metastatic malignant GIST.
The primary objective of the 2 studies was to evaluate either progression-free survival (PFS) with a secondary objective of overall survival (OS) in 1 study (EORTC) or OS with a secondary objective of PFS in the other study (SWOG). A planned analysis of both OS and PFS from the combined datasets from these 2 studies was conducted. Results from this combined analysis are shown in Table 8. (See Table 8.)

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Median follow-up for the combined studies was 37.5 months (25th-75th percentile 19-46 months). There was a statistically significant improvement in PFS in the 800-mg treatment group [23.2 months (95% CI, 20.8-24.9)] compared to the 400-mg treatment group [18.9 months (95% CI, 17.4-21.2)] (p=0.03). However, there were no observed differences in overall survival between the treatment groups (p=0.98). The estimated overall PFS for all 1640 patients in these phase III studies was 21 months (95% CI, 19.4-22.5) and the estimated OS of 48.8 months (95% CI, 46.3-51.6). 5.1% of patients achieved a confirmed complete response and 47.5% achieved a partial response. Treatment at either dose level was generally well tolerated and overall 5.4% of patients withdrew due to toxicity.
Patients who crossed over following disease progression from the 400-mg/day treatment group to the 800-mg/day treatment (n=347) had a 3.4-month median and 7.7-month mean exposure to Glivec following crossover. Overall survival of patients following crossover was 14.3 months (95% CI, 12.2-16.7) and 19.3% of these patients were still alve at 48 months.
One phase II, open-label, randomized, multinational study was conducted in patients with unresectable or metastatic malignant GIST. In this study, 147 patients were enrolled and randomized to receive either 400 or 600 mg orally once daily for up to 36 months. These patients ranged in age from 18-83 years and had a pathologic diagnosis of Kit-positive malignant GIST that was unresectable and/or metastatic.
The primary evidence of efficacy was based on objective response rates. Tumours were required to be measurable in at least 1 site of disease, and response characterization, based on Southwestern Oncology Group (SWOG) criteria. In this study, 83% of the patients achieved either a complete response, partial response or stable disease. Results are provided in Table 9. (See Table 9.)

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There were no differences in response rates between the 2 dose groups. A significant number of patients who had stable disease at the time of the interim analysis achieved a partial response with longer treatment (median follow-up 31 months). Median time to response was 13 weeks (95% CI, 12-23). Median time to treatment failure in responders was 122 weeks (95% CI, 106-147), while in the overall study population it was 84 weeks (95% CI, 71-109). The median overall survival has not been reached. The Kaplan-Meier estimate for survival after 36-month follow-up is 68%. Additionally, there is no difference in survival between patients achieving stable disease and partial response.
Clinical Study in Adjuvant GIST: In the adjuvant setting, Glivec was investigated in a multicentre, double-blind, long-term, placebo-controlled phase III study ( ACOSOG Z9001 trial) involving 713 patients. The ages of these patients ranged from 18-91 years. Patients were included who had a histologic diagnosis of primary GIST expressing KIT protein by immunochemistry and a tumour size ≥3 cm in maximum dimension, with complete gross resection of primary GIST within 14-70 days prior to registration. After resection of primary GIST, patients were randomized to 1 of the 2 arms: Glivec at 400 mg/day (n=359) or matching placebo (n=354) for 1 year.
The primary endpoint of the study was recurrence free survival (RFS) defined as the time from date of randomization to the date of recurrence or death from any cause.
Glivec prolonged significantly RFS with 75% of patients being recurrence-free at 38 months in the Glivec group versus 20 months in the placebo group [95% CIs, (30 non-estimable); (14 non-estimable), respectively]; [hazard ratio=0.398 (0.259-0.61), p<0.0001]. At 1 year, the overall RFS was significantly better for Glivec (97.7%) versus placebo (82.3%), (p<0.0001) therefore reducing the risk of recurrence by approximately 89% compared with placebo [hazard ratio=0.113 (0.049-0.264)]. With only 13 events observed, the overall survival rate at 2nd year was not statistically significant (98.8% versus 97.6%) between the 2 treatment groups. This is expected given the limited follow-up of the trial to date.
Clinical Studies in DFSP: One open-label, multicentre, phase II clinical trial (study B2225) was conducted testing Glivec in a diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR-protein tyrosine kinases. This study included 12 patients with DFSP out of a total of 185 patients, 45 of whom had haematological diseases and 140 a variety of solid tumours. The primary evidence of efficacy for patients in the solid tumour group was based on objective response rates. The solid tumour population was treated with Glivec 800 mg daily. The age of the DFSP patients ranged from 23-75 years; DFSP was metastatic, locally recurrent following initial resective surgery and not considered amenable to further resective surgery at the time of the study entry. A further 6 DFSP patients treated with Glivec are reported in 5 published case reports, their ages ranging from 18 months to 49 years. The total population treated for DFSP comprises 18 patients, 8 of them with metastatic disease. The adult patients reported in the published literature were treated with either Glivec 400 mg (4 cases) or 800 mg (1 case) daily. The paediatric patient received 400 mg/m2/day, subsequently increased to 520 mg/m2/day. Responses to treatment are described in Table 10. (See Table 10.)

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Twelve of these 18 patients either achieved a complete response (7 patients) or were made disease-free by surgery after a partial response (5 patients, including 1 child) for a total complete response rate of 67%. A further 3 patients achieved a partial response, for an overall response rate of 83%. Of the 8 patients with metastatic disease, 5 responded (62%), 3 of them completely (37%). The median duration of therapy in study B2225 was 6.2 months, with a maximum duration of 24.3 months, while in the published literature it ranged between 4 weeks and >20 months.
Clinical Studies in Hepatic Insufficiency: In a study of patients with varying degrees of hepatic dysfunction (mild, moderate and severe) (see Table 11 for liver function classification), the mean exposure to imatinib (dose normalized AUC) did not increase compared to patients with normal liver function. In this study, 500 mg daily was safely used in patients with mild liver dysfunction and 300 mg daily was used in other patients. Although only a 300 mg daily dose was used in patients with moderate and severe liver dysfunction, pharmacokinetic analysis projects that 400 mg can be used safely (see Pharmacokinetics under Actions, Dosage & Administration, Precautions and Adverse Reactions). (See Table 11.)

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Clinical Studies in Renal Insufficiency: In a study of patients with varying degrees of renal dysfunction [mild, moderate and severe (see Table 12 for renal function classification)], the mean exposure to imatinib (dose normalized AUC) increased 1.5- to 2-fold compared to patients with normal renal function, which corresponded to an elevated plasma level of AGP, a protein to which imatinib binds strongly. No correlation between imatinib exposure and the severity of renal deficiency was observed. In this study, 800 mg daily was safely used in patients with mild renal dysfunction and 600 mg daily was used in moderate renal dysfunction. The 800-mg dose was not tested in patients with moderate renal dysfunction due to the limited number of patients enrolled. Similarly, only 2 patients with severe renal dysfunction were enrolled at the low (100 mg) dose, and no higher doses were tested. No patients on haemodialysis were enrolled in the study. Literature data showed that a daily dose of 400 mg was well tolerated in a patient with end-stage renal disease on haemodialysis. The PK plasma exposure in this patient fell within the range of values of imatinib and its metabolite CGP74588 observed in patients with normal renal function. Dialysis was not found to intervene with the plasma kinetics of imatinib. Since renal excretion represents a minor elimination pathway for imatinib, patients with severe renal insufficiency and on dialysis could receive treatment at the 400-mg starting dose. However, in these patients, caution is recommended. The dose can be reduced if not tolerated or increased for lack of efficacy (see Pharmacokinetics under Actions, Dosage & Administration, and Precautions). (See Table 12.)

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Pharmacokinetics: The pharmacokinetics of Glivec have been evaluated over a dosage range of 25-1000 mg. Plasma pharmacokinetic profiles were analysed on day 1 and on either day 7 or 28, by which time plasma concentrations had reached steady-state.
Absorption: Mean absolute bioavailability for imatinib is 98%. The coefficient of variation for plasma imatinib AUC is in the range of 40-60% after an oral dose. When given with a high fat meal, the rate of absorption of imatinib was minimally reduced (11% decrease in Cmax and prolongation of tmax by 1.5 hrs), with a small reduction in AUC (7.4%) compared to fasting conditions.
Distribution: At clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95% on the basis of in vitro experiments, mostly to albumin and α-acid-glycoprotein (AGP), with little binding to lipoprotein.
Metabolism: The main circulating metabolite in humans is the N-demethylated piperazine derivative (CGP71588) which shows similar in vitro potency as the parent compound. The plasma AUC for this metabolite was found to be only 16% of the AUC for imatinib. The plasma protein-binding of the N-demethylated metabolite is similar to that of the parent compound.
Elimination: Based on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81% of the dose was eliminated within 7 days in the faeces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% faeces), the remainder being metabolites.
Plasma Pharmacokinetics: Following oral administration in healthy volunteers, the t½ was approximately 18 hrs, suggesting that once-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose proportional in the range of 25-1000 mg imatinib after oral administration. There was no change in the kinetics of imatinib on repeated dosing and accumulation was 1.5- to 2.5-fold at steady-state when dosed once daily.
Population Pharmacokinetics: Based on population pharmacokinetic analysis, there was a small effect of age on the volume of distribution (12% increase in patients >65 years). This change is not thought to be clinically significant. The effect of body weight on the clearance of imatinib is such that for a patient weighing 50 kg, the mean clearance is expected to be 8.5 L/hr, while for a patient weighing 100 kg, the clearance will rise to 11.8 L/hr. These changes are not considered sufficient to warrant dose adjustment based on kg body weight. There is no effect of gender on the kinetics of imatinib.
Further population PK analysis in the phase III study in newly diagnosed CML patients showed that the effect of covariates and comedications on both clearance and volume appears to be small and is not sufficiently pronounced to warrant dose adjustment.
Pharmacokinetics in Children: As in adult patients, imatinib was rapidly absorbed after oral administration in paediatric patients in both phase I and phase II studies. Dosing in children at 260 and 340 mg/m2 achieved the same exposure, respectively, as doses of 400 and 600 mg in adult patients. The comparison of AUC(0-24) on day 8 and day 1 at 340 mg/m2 dose level revealed a 1.7-fold drug accumulation after repeated once-daily dosing.
Organ Function Impairment: Imatinib and its metabolites are not excreted via the kidney to a significant extent. Patients with mild and moderate impairment of renal function appear to have a higher plasma exposure than patients with normal renal function. The increase is approximately 1.5- to 2-fold, corresponding to a 1.5-fold elevation of plasma AGP, to which imatinib binds strongly. The free drug clearance of imatinib is probably similar between patients with renal impairment and those with normal renal function, since renal excretion represents only a minor elimination pathway for imatinib (see Pharmacodynamics under Actions, Dosage & Administration, and Precautions).
Although the results of pharmacokinetic analysis showed that there is considerable intersubject variation, the mean exposure to imatinib did not increase in patients with varying degrees of liver dysfunction as compared to patients with normal liver function (see Dosage & Administration, Precautions, Adverse Reactions, and Pharmacology and Pharmacokinetics under Actions).
Toxicology: Preclinical Safety Data: Imatinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity and reproductive toxicity studies. Target organs associated with the pharmacological action of imatinib include bone marrow, peripheral blood, lymphoid tissues, gonads and gastrointestinal tract. Other target organs include the liver and kidney.
Imatinib was embryotoxic and teratogenic in rats.
In the 2-year rat carcinogenicity study, administration of imatinib at 15, 30 and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at ≥30 mg/kg/day. Histopathological examination of decedents revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Target organs for neoplastic changes were the kidneys, urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-glandular stomach. The no-observed-effect levels (NOEL) for the various target organs with neoplastic lesions were established as follows: 30 mg/kg/day for the kidneys, urinary bladder, urethra, small intestine, parathyroid glands, adrenal glands and non-glandular stomach and 15 mg/kg/day for the preputial and clitoral gland.
The papilloma/carcinoma of the preputial/clitoral gland were noted at 30 and 60 mg/kg/day, representing approximately 0.5-4 or 0.3-2.4 times the human daily exposure (based on AUC) at 400 or 800 mg/day, respectively, and 0.4-3 times the daily exposure in children (based on AUC) at 340 mg/m2. The renal adenoma/carcinoma, urinary bladder and urethra papilloma, small intestine adenocarcinomas, parathyroid gland adenomas, benign and malignant medullary tumours of the adrenal glands and non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day.
The relevance of these findings in the rat carcinogenicity study for humans is not known. An analysis of the safety data from clinical trials and spontaneous adverse event reports did not provide evidence of an increase in overall incidence of malignancies in patients treated with imatinib compared to that of the general population.
Non-neoplastic lesions not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals.
Indications/Uses
Treatment of adult and paediatric patients with newly diagnosed chronic myeloid leukaemia (CML); CML in blast crisis, accelerated phase or in chronic phase after failure of interferon-α therapy (for paediatric use, see Dosage & Administration).
Treatment of adult patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy; relapsed or refractory Ph+ ALL; myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene rearrangements; systemic mastocytosis (SM) without the D816V c-Kit mutation or with c-Kit mutational status unknown; hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL); unresectable and/or metastatic malignant gastrointestinal stromal tumours (GIST); unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP).
Adjuvant treatment of adult patients following resection of GIST with a tumour size of ≥3 cm.
The effectiveness of Glivec is based on overall haematological and cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on haematological response rates in SM, HES/CEL and on objective response rates and progression-free survival in unresectable and/or metastatic GIST, on recurrence-free survival in adjuvant GIST and on objective response rates in DFSP (see Pharmacodynamics under Actions). Increased survival in controlled trials has been demonstrated only in newly diagnosed chronic phase CML and GIST.
Dosage/Direction for Use
Therapy should be initiated by a physician experienced in the treatment of patients with haematological malignancies and malignant sarcomas, as appropriate.
The prescribed dose should be administered orally with a meal and a large glass of water. Doses of 400 or 600 mg should be administered once daily, whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and evening.
For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100-mg tab and 200 mL for a 400-mg tab) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s).
CML: Recommended Dose: 400 mg/day for patients in chronic phase CML and 600 mg/day for patients in accelerated phase or blast crisis.
Treatment should be continued as long as the patient continues to benefit.
Increase dose from 400-600 or 800 mg in patients with chronic phase disease, or from 600 mg to a maximum of 800 mg daily in patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe nonleukaemia-related neutropenia or thrombocytopenia in the following circumstances: Disease progression (at any time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved haematological and/or cytogenetic response.
Children: Dosing in children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily is recommended for children with chronic phase and advanced phase CML (not to exceed the total dose of 600 mg daily). Treatment can be given as a once-daily dose or alternatively, the daily dose may be split into 2 administrations, 1 in the morning and 1 in the evening. The dose recommendation is currently based on a small number of paediatric patients (see Pharmacology and Pharmacokinetics under Actions). There is no experience with the use of Glivec in children <2 years.
Ph+ALL: Recommended Dose: 600 mg/day.
MDS/MPD: Recommended Dose: 400 mg/day.
SM: Recommended Dose: 400 mg/day for patients with SM without the D816V c-Kit mutation. If c-Kit mutational status is not known or unavailable, treatment with Glivec at dose of 400 mg/day may be considered for patients with SM not responding satisfactorily to other therapies.
For patients with SM associated with eosinophilia, a clonal haematological disease related to the fusion kinase FIP1L1-PDGFR-α, starting dose of 100 mg/day is recommended. A dose increase from 100-400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
HES/CEL: Recommended Dose: 400 mg/day.
For HES/CEL patients with demonstrated FIP1L1-PDGFR-α fusion kinase, a starting dose of 100 mg/day is recommended. A dose increase from 100-400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.
GIST: 400 mg/day for patients with unresectable and/or metastatic, malignant GIST.
A dose increase from 400-600 or 800 mg for patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. Treatment with Glivec in GIST patients should be continued until disease progression.
Adjuvant Treatment of Adult Patients Following Resection of GIST: 400 mg/day. In the adjuvant setting, the optimal treatment duration with Glivec is not known.
DFSP: Recommended Dose: 800 mg/day. Dose Adjustments for Adverse Reactions: Nonhaematological Adverse Reactions: If a severe nonhaematological adverse reaction develops with Glivec use, treatment must be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.
If elevations in bilirubin >3 times institutional upper limit of normal (IULN) or in liver transaminases >5 x IULN occur, Glivec should be withheld until bilirubin levels have returned to a <1.5 x IULN and transaminase levels to <2.5 x IULN. Treatment with Glivec may then be continued at a reduced daily dose. In adults, the dose should be reduced from 400 to 300 mg, or from 600 to 400 mg, or from 800 to 600 mg, and in children from 340 to 260 mg/m2/day.
Haematological Adverse Reactions: Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in Table 13. (See Table 13.)

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Children: There is no experience with the use of Glivec in children with CML <2 years.
There is very limited experience with the use of Glivec in children <3 years in other indications.
Hepatic Insufficiency: Imatinib is mainly metabolised through the liver. Patients with mild, moderate or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The dose can be reduced if not tolerated (see Pharmacology and Pharmacokinetics under Actions, Precautions and Adverse Reactions).
Renal Insufficiency: Imatinib and its metabolites are not significantly excreted via the kidney. Since the renal clerance of imatinib is negligible, a decrease in free drug clearance is not expected in patients with renal insufficiency. Patients with mild or moderate renal dysfunction should be given the minimum recommended dose of 400 mg daily as starting dose. Although very limited information is available (see Pharmacology and Pharmacokinetics under Actions), patients with severe renal dysfunction or on dialysis could also start at the same dose of 400 mg. However, in these patients, caution is recommended. The dose can be reduced if not tolerated or increased for lack of efficacy (see Precautions).
Elderly: No significant age-related pharmacokinetic differences have been observed in adult patients in clinical trials which included >20% of patients ≥65 years. No specific dose recommendation is necessary in the elderly.
Overdosage
Experience with doses >800 mg is limited. Isolated cases of Glivec overdosage have been reported. In the event of overdosage, the patient should be observed and appropriate supportive treatment given.
A patient with myeloid blast crisis inadvertently took Glivec 1200 mg for 6 days and experienced grade 1 elevations of serum creatinine, grade 2 ascites and elevated liver transaminase levels, and grade 3 elevations of bilirubin. Treatment was temporarily interrupted and there was complete reversal of all abnormalities within 1 week. Treatment was resumed at a dose of 400 mg without recurrence of problems. Another patient developed severe muscle cramps after taking Glivec 1600 mg daily for 6 days. Following interruption of treatment, complete resolution of muscle cramps occurred and treatment was subsequently resumed. Another patient who was prescribed 400 mg daily took Glivec 800 mg on day 1 and 1200 mg on day 2. Treatment was interrupted, no adverse events occurred and the patient resumed treatment.
Contraindications
Hypersensitivity to imatinib mesilate or to any of the excipients of Glivec.
Special Precautions
Glivec should be taken with food and a large glass of water to minimise the risk of gastrointestinal disturbances.
When Glivec is co-administered with other medications, there is a potential for drug interactions (see Interactions).
One patient, who was taking paracetamol/acetaminophen regularly for fever, died of acute liver failure. Although the aetiology is currently unknown, special caution should be exercised when using paracetamol/acetaminophen (see Interactions).
Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Glivec. Thyroid-stimulating hormone (TSH) levels should be closely monitored in such patients.
In patients with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liver enzymes should be carefully monitored (see Pharmacology and Pharmacokinetics under Actions, Dosage & Administration and Adverse Reactions).
When imatinib is combined with high-dose chemotherapy regimens, transient liver toxicity in the form of transaminase elevation and hyperbilirubinaemia has been observed. Additionally, there have been uncommon reports of acute liver failure. Monitoring of hepatic function is recommended in circumstances where imatinib is combined with chemotherapy regimens also known to be associated with hepatic dysfunction (see Adverse Reactions).
Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, superficial oedema) have been reported in approximately 2.5% of newly diagnosed CML patients taking Glivec. Therefore, it is recommended that patients be weighed regularly. An unexpected rapid weight gain should be carefully investigated and if necessary, appropriate supportive care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence of these events in elderly patients and those with a prior history of cardiac disease.
Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated.
In patients with hypereosinophilic syndrome (HES) and cardiac involvement, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of imatinib therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib. Myelodysplastic/myeloproliferative diseases and systemic mastocytosis might be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or SM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for 1-2 weeks concomitantly with imatinib should be considered at the initiation of therapy.
In the phase III GIST studies in patients with unresectable or metastatic malignant GIST 211 patients (12.9%) reported grade 3/4 haemorrhage at any site. In the phase II GIST study in patients with unresectable or metastatic malignant GIST (study B2222), 8 patients (5.4%) were reported to have had gastrointestinal (GI) haemorrhage and 4 patients (2.7%) were reported to have had haemorrhages at the site of tumour deposits. The tumour haemorrhages have been either intra-abdominal or intrahepatic, depending on the anatomical location of tumour lesions. Gastrointestinal sites of tumour may have contributed to reports of GI bleeding in this patient population (see Adverse Reactions).
Laboratory Tests: Complete blood counts must be performed regularly during therapy with Glivec. Treatment of CML patients with Glivec has been associated with neutropenia or thrombocytopenia. However, the occurrence of these cytopenias is dependent on the stage of the disease being treated and they were more frequent in patients with accelerated phase CML or blast crisis as compared to patients with chronic phase CML. Treatment with Glivec may be interrupted or the dose be reduced, as recommended under Dosage & Administration.
Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving Glivec. As recommended in Dosage & Administration nonhaematological adverse reactions, these laboratory abnormalities should be managed with interruption and/or dose reduction of the treatment with Glivec.
Glivec and its metabolites are not excreted via the kidney to a significant extent. Creatinine clearance (CrCl) is known to decrease with age, and age did not significantly affect Glivec kinetics. In patients with impaired renal function, imatinib plasma exposure seems to be higher than that in patients with normal renal function, probably due to an elevated plasma level of α-acid glycoprotein (AGP), an imatinib-binding protein, in these patients. There is no correlation between imatinib exposure and the degree of renal impairment, as classified by the measurement of CrCl, between patients with mild (CrCl 40-59 ml/min) and severe (CrCl <20 ml/min) renal impairment. However, as recommended in Dosage & Administration, the starting dose of imatinib can be reduced if not tolerated.
Women of Childbearing Potential: Women of childbearing potential must be advised to use effective contraception during treatment.
Effects on the Ability to Drive or Operate Machinery: While no specific reports have been received, patients should be advised that they may experience undesirable effects eg, dizziness or blurred vision during treatment with imatinib. Therefore, caution should be recommended when driving a car or operating machinery.
Use in Pregnancy: There are no adequate data on the use of imatinib in pregnant women. Studies in animals have, however, shown reproductive toxicity (see Toxicology under Actions) and the potential risk for the foetus is unknown. Glivec should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.
Use in Lactation: It is not known whether imatinib is excreted in human milk. In animals, imatinib and/or its metabolites were extensively excreted in milk. Women who are taking Glivec should therefore not breastfeed.
Use In Pregnancy & Lactation
Use in Pregnancy: There are no adequate data on the use of imatinib in pregnant women. Studies in animals have, however, shown reproductive toxicity (see Toxicology under Actions) and the potential risk for the foetus is unknown. Glivec should not be used during pregnancy unless clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.
Use in Lactation: It is not known whether imatinib is excreted in human milk. In animals, imatinib and/or its metabolites were extensively excreted in milk. Women who are taking Glivec should therefore not breastfeed.
Adverse Reactions
Patients with advanced stages of malignancies may have numerous confounding medical conditions that make causality of adverse events difficult to assess due to the variety of symptoms related to the underlying disease, its progression and the co-administration of numerous medications.
Glivec was generally well tolerated with chronic oral daily dosing in patients with CML including paediatric patients. The majority of adult patients experienced adverse events at some point in time, but most were of mild to moderate grade, and in clinical trials, drug discontinuation for drug-related adverse events was observed in 2.4% of newly diagnosed patients, 4% of patients in late chronic phase after failure of interferon therapy, 4% of patients in accelerated phase after failure of interferon therapy and 5% of blast crisis patients after failure of interferon therapy. In the GIST study (B2222), Glivec was discontinued for drug-related adverse events in 4% of patients.
The adverse reactions were similar in all indications, with 2 exceptions. There was less myelosuppression in GIST and intratumoral haemorrhage was only seen in the GIST population (see Precautions). The most frequently reported drug-related adverse events were mild nausea, vomiting, diarrhoea, myalgia, muscle cramps and rash, which were easily manageable. Superficial oedemas were a common finding in all studies and were described primarily as periorbital or lower limb oedemas. However, these oedemas were rarely severe and may be managed with diuretics, other supportive measures or in some patients by reducing the dose of Glivec.
Overall, the incidence of all grades of adverse reactions and the incidence of severe adverse reactions were similar between 400- and 800-mg treatment groups except for oedema, which was reported more frequently in the 800-mg group in the phase III studies in patients with unresectable or metastatic malignant GIST (SWOG, EORTC studies).
When imatinib was combined with high-dose chemotherapy in Ph+ ALL patients, transient liver toxicity in the form of transaminase elevation and hyperbilirubinaemia were observed.
Miscellaneous adverse events eg, pleural effusion, ascites, pulmonary oedema and rapid weight gain with or without superficial oedema may be collectively described as "fluid retention". These events can usually be managed by withholding Glivec temporarily and/or with diuretics and/or other appropriate supportive care measures. However, a few of these events may be serious or life-threatening and several patients with blast crisis died with a complex clinical history of pleural effusion, congestive heart failure and renal failure.
Adverse reactions listed as follows are ranked under headings of frequency, the most frequent first, using the following convention: 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), including isolated reports. Adverse reactions and their frequencies are based on the registration studies for CML and GIST.
Adverse Reactions in Clinical Studies for CML and GIST: Infections and Infestations: Uncommon: Herpes zoster, herpes simplex, nasopharyngitis, pneumonia (reported most commonly in patients with transformed CML and in patients with GIST), sinusitis, cellulitis, upper respiratory tract infection, influenza, urinary tract infection, gastroenteritis, sepsis. Rare: Fungal infection.
Blood and Lymphatic System Disorders: Very Common: Neutropenia, thrombocytopenia, anaemia. Common: Pancytopenia, febrile neutropenia. Uncommon: Thrombocythaemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy. Rare: Haemolytic anaemia.
Metabolism and Nutrition Disorders: Common: Anorexia. Uncommon: Hypokalaemia, increased appetite, hypophosphataemia, decreased appetite, dehydration, gout, hyperuricaemia, hypercalcaemia, hyperglycaemia, hyponatraemia. Rare: Hyperkalaemia, hypomagnesaemia.
Psychiatric Disorders: Common: Insomnia. Uncommon: Depression, decreased libido, anxiety. Rare: Confusional state.
Nervous System Disorders: Very Common: Headache (most common in GIST patients). Common: Dizziness, paraesthesia, taste disturbance, hypoaesthesia. Uncommon: Migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome, tremor, cerebral haemorrhage. Rare: Increased intracranial pressure, convulsions, optic neuritis.
Eye Disorders: Eyelid oedema, increased lacrimation, conjunctival haemorrhage, conjunctivitis, dry eye, blurred vision. Uncommon: Eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinal haemorrhage, blepharitis, macular oedema. Rare: Cataract, glaucoma, papilloedema.
Ear and Labyrinth Disorders: Uncommon: Vertigo, tinnitus, hearing loss.
Cardiac Disorders: Uncommon: Palpitations, tachycardia, congestive cardiac failure (on a patient-year basis, cardiac events including congestive heart failure were more commonly observed in patients with transformed CML than in patients with chronic CML), pulmonary oedema. Rare: Arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion.
Vascular Disorders: Common: Flushing, haemorrhage. Uncommon: Hypertension, haematoma, peripheral coldness, hypotension, Raynaud's phenomenon.
Respiratory, Thoracic and Mediastinal Disorders: Common: Dyspnoea, epistaxis, cough. Uncommon: Pleural effusion [reported more commonly in patients with GIST and in patients with transformed CML (CML-AP and CML-BC) than in patients with chronic CML], pharyngolaryngeal pain, pharyngitis. Rare: Pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhage.
Gastrointestinal Disorders: Very Common: Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain (most commonly observed in GIST patients). Common: Flatulence, abdominal distension, gastro-oesophageal reflux, constipation, dry mouth, gastritis. Uncommon: Stomatitis, mouth ulceration, gastrointestinal haemorrhage (most commonly observed in GIST patients), eructation, melaena, oesophagitis, ascites, gastric ulcer, haematemesis, cheilitis, dysphagia, pancreatitis. Rare: Colitis, ileus, inflammatory bowel disease.
Hepatobiliary Disorders: Common: Increased hepatic enzymes. Uncommon: Hyperbilirubinaemia, hepatitis, jaundice. Rare: Hepatic failure, hepatic necrosis (some fatal cases have been reported).
Skin and Subcutaneous Tissue Disorders: Very Common: Periorbital oedema, dermatitis/eczema/rash. Common: Pruritus, face oedema, dry skin, erythema, alopecia, night sweats, photosensitivity reaction. Uncommon: Pustular rash, contusion, increased sweating, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, exfoliative dermatitis, onychoclasis, folliculitis, petechiae, psoriasis, purpura, skin hyperpigmentation, bullous eruptions. Rare: Acute febrile neutrophilic dermatosis (Sweet's syndrome), nail discolouration, angioneurotic oedema, vesicular rash, erythema multiforme, leucocytoclastic vasculitis, Stevens-Johnson syndrome.
Musculoskeletal and Connective Tissue Disorders: Very Common: Muscle spasms and cramps, musculoskeletal pain including myalgia, arthralgia, bone pain (more commonly observed in patients with CML than in GIST patients). Common: Joint swelling. Uncommon: Joint and muscle stiffness. Rare: Muscular weakness, arthritis.
Renal and Urinary Disorders: Uncommon: Renal pain, haematuria, acute renal failure, increased urinary frequency.
Reproductive System and Breast Disorders: Uncommon: Gynaecomastia, erectile dysfunction, menorrhagia, irregular menstruation, sexual dysfunction, nipple pain, breast enlargement, scrotal oedema.
General Disorders and Administration Site Conditions: Very Common: Fluid retention and oedema, fatigue. Common: Weakness, pyrexia, anasarca, chills, rigors. Uncommon: Chest pain, malaise.
Investigations: Very Common: Increased weight. Common: Decreased weight. Uncommon: Increased blood creatinine, blood creatine phosphokinase, blood lactate dehydrogenase, blood alkaline phosphatase. Rare: Increased blood amylase.
The following types of reactions have been reported from post-marketing experience and from additional clinical studies with Glivec. They include spontaneous case reports as well as serious adverse events from smaller or ongoing clinical studies and the expanded access programmes. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to imatinib exposure.
Adverse Reactions from Post-Marketing Reports: Nervous System Disorders: Uncommon: Cerebral oedema.
Eye Disorders: Rare: Vitreous haemorrhage.
Cardiac Disorders: Rare: Pericarditis, cardiac tamponade.
Vascular Disorders: Uncommon: Thrombosis/embolism. Very Rare: Anaphylactic shock.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Acute respiratory failure (fatal cases have been reported in patients with advanced disease, severe infections, severe neutropenia and other serious concomitant conditions), interstitial lung disease.
Gastrointestinal Disorders: Uncommon: Ileus/intestinal obstruction, tumour haemorrhage/tumour necrosis, gastrointestinal perforation (some fatal cases have been reported). Rare: Diverticulitis.
Skin and Subcutaneous Tissue Disorders: Rare: Lichenoid keratosis, lichen planus. Very rare: Toxic epidermal necrolysis.
Musculoskeletal and Connective Tissue Disorders: Rare: Avascular necrosis/hip osteonecrosis.
Laboratory Test Abnormalities: Haematology: In CML cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in all studies, with the suggestion of a higher frequency at high doses ≥750 mg (phase I study). However, the occurrence of cytopenias was also clearly dependent on the stage of the disease. In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients. The frequency of grade 3 or 4 neutropenias (ANC <1 x 109/L) and thrombocytopenias (platelet count <50 x 109/L) being between 4 and 6 times higher in blast crisis and accelerated phase (59-64% and 44-63% for neutropenia and thrombocytopenia, respectively) as compared to newly diagnosed patients in chronic phase CML (16.7% neutropenia and 8.9% thrombocytopenia). In newly diagnosed chronic phase CML grade 4 neutropenia (ANC <0.5 x 109/L) and thrombocytopenia (platelet count <10 x 109/L) were observed in 3.6% and <1% of patients, respectively. The median duration of the neutropenic and thrombocytopenic episodes usually ranged from 2-3 weeks and from 3-4 weeks, respectively. These events can usually be managed with either a reduction of the dose or an interruption of treatment with Glivec, but can in rare cases lead to permanent discontinuation of treatment. In paediatric CML patients, the most frequent toxicities observed were grade 3 or 4 cytopenias involving neutropenia, thrombocytopenia and anaemia. These generally occur within the first several months of therapy.
In patients with unresectable or metastatic malignant GIST (study B2222), grade 3 and 4 anaemia were reported in 5.4% and 0.7% of patients, respectively, and may have been related to gastrointestinal or intratumoral bleeding in at least some of these patients. Grade 3 and 4 neutropenia were seen in 7.5% and 2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient developed grade 4 thrombocytopenia. The decreases in white blood cells (WBC) and neutrophil counts occurred mainly during the first 6 weeks of therapy, with values remaining relatively stable thereafter.
Biochemistry: Severe elevation of transaminases (<5%) or bilirubin (<1%) was seen in CML patients and was usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in <1% of CML patients. In GIST patients (study B2222), 6.8% of grade 3 or 4 serum glutamic pyruvic transferase (SGPT) elevations and 4.8% of grade 3 or 4 serum glutamic oxaloacetic transferase (SGOT) elevations were observed. Bilirubin elevation was <3%.
There have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some of them outcome was fatal.
Drug Interactions
Drugs That May Increase Imatinib Plasma Concentrations: Substances that inhibit the cytochrome P-450 isoenzyme CYP3A4 activity (eg, ketoconazole, itraconazole, erythromycin, clarithromycin) could decrease metabolism and increase imatinib concentrations. There was a significant increase in exposure to imatinib (the mean Cmax and AUC of imatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a single dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering Glivec with inhibitors of the CYP3A4 family.
Drugs That May Decrease Imatinib Plasma Concentrations: Substances that are inducers of CYP3A4 activity could increase metabolism and decrease imatinib plasma concentrations. Co-medications which induce CYP3A4 (eg, dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St. John's wort) may significantly reduce exposure to Glivec. Pre-treatment of 14 healthy volunteers with multiple doses of rifampin, 600 mg daily for 8 days, followed by a single dose of Glivec 400 mg, increased Glivec oral dose clearance by 3.8-fold (90% confidence interval = 3.5- to 4.3-fold), which represents mean decreases Cmax, AUC(0-24) and AUC(0-∞) by 54%, 68% and 74%, of the respective values without rifampin treatment. Similar results were observed in patients with malignant gliomas treated with Glivec while taking enzyme-inducing antiepileptic drugs (EIAEDs) eg, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital and primidone. The plasma AUC for imatinib decreased by 73% compared to patients not on EIAEDs. In 2 published studies, concomitant administration of imatinib and a product containing St. John's wort led to a 30-32% reduction in the AUC of Glivec. In patients where rifampin or other CYP3A4 inducers are indicated, alternative therapeutic agents with less enzyme induction potential should be considered.
Drugs That May Have Their Plasma Concentration Altered by Glivec: Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended when administering Glivec with CYP3A4 substrates with a narrow therapeutic window (eg, cyclosporin or pimozide). Glivec may increase plasma concentration of other CYP3A4-metabolised drugs (eg, triazolobenzodiazepines, dihydropyridine, calcium-channel blockers, certain HMG-CoA reductase inhibitors ie, statins, etc).
Imatinib also inhibits CYP2C9 and CYP2C19 activity in vitro. Prothrombin time (PT) prolongation was observed following co-administration with warfarin. When giving coumarins, short-term PT monitoring is therefore necessary at the start and end of Glivec therapy and when altering the dosage. Alternatively, the use of low-molecular weight heparin should be considered.
In vitro, Glivec inhibits the cytochrome P-450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4 activity. Imatinib at 400 mg twice daily had a weak inhibitory effect on CYP2D6-mediated metropolol metabolism, with metoprolol Cmax and AUC being increased by approximately 23%. Co-administration of imatinib with CYP2D6 substrates eg, metoprolol, does not seem to be a risk factor for drug-drug interactions and dose adjustment may not be necessary. In vitro, Glivec inhibits paracetamol/acetaminophen O-glucuronidation (KI value of 58.5 micromol/L at therapeutic levels) (see Precautions).
Incompatibilities: Not applicable.
ATC Classification
L01EA01 - imatinib ; Belongs to the class of BCR-ABL tyrosine kinase inhibitors. Used in the treatment of cancer.
Presentation/Packing
FC tab 100 mg (very dark yellow to brownish-orange, round with imprint “NVR” on one side and “SA” and scored on the other) x 60's. 400 mg (not divisible, very dark yellow to brownish-orange, ovaloid, biconvex with bevelled edges, debossed with “NVR” on one side and “SL” on the other) x 30's.
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