Glivec

Overdose

Experience with doses higher than the recommended therapeutic dose is limited. Isolated cases of Glivec overdose have been reported spontaneously and in the literature. In the event of overdose the patient should be observed and appropriate symptomatic treatment given. Generally the reported outcome in these cases was “improved” or “recovered”. Events that have been reported at different dose ranges are as follows:

Adult population

1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine phosphokinase, increased bilirubin, gastrointestinal pain.

6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, increased transaminases.

8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Paediatric population

One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhoea.

In the event of overdose, the patient should be observed and appropriate supportive treatment given.

Shelf life

3 years

Glivec price

Incompatibilities

Not applicable.

List of excipients

Tablet core:

Cellulose microcrystalline

Crospovidone

Hypromellose

Magnesium stearate

Silica, colloidal anhydrous

Tablet coat:

Iron oxide, red (E172)

Iron oxide, yellow (E172)

Macrogol

Talc

Hypromellose

Preclinical safety data

The preclinical safety profile of imatinib was assessed in rats, dogs, monkeys and rabbits.

Multiple dose toxicity studies revealed mild to moderate haematological changes in rats, dogs and monkeys, accompanied by bone marrow changes in rats and dogs.

The liver was a target organ in rats and dogs. Mild to moderate increases in transaminases and slight decreases in cholesterol, triglycerides, total protein and albumin levels were observed in both species. No histopathological changes were seen in rat liver. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia.

Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralisation and dilation of the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were observed in several of these animals. In rats, hyperplasia of the transitional epithelium in the renal papilla and in the urinary bladder was observed at doses > 6 mg/kg in the 13-week study, without changes in serum or urinary parameters. An increased rate of opportunistic infections was observed with chronic imatinib treatment.

In a 39-week monkey study, no NOAEL (no observed adverse effect level) was established at the lowest dose of 15 mg/kg, approximately one-third the maximum human dose of 800 mg based on body surface. Treatment resulted in worsening of normally suppressed malarial infections in these animals.

Imatinib was not considered genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus test. Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberration) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay.

In a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. This was not seen at doses ≤ 20 mg/kg. A slight to moderate reduction in spermatogenesis was also observed in the dog at oral doses > 30 mg/kg. When female rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect on mating or on number of pregnant females. At a dose of 60 mg/kg, female rats had significant post-implantation foetal loss and a reduced number of live foetuses. This was not seen at doses ≤ 20 mg/kg.

In an oral pre- and postnatal development study in rats, red vaginal discharge was noted in the 45 mg/kg/day group on either day 14 or day 15 of gestation. At the same dose, the number of stillborn pups as well as those dying between postpartum days 0 and 4 was increased. In the F1 offspring, at the same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. F1 fertility was not affected, while an increased number of resorptions and a decreased number of viable foetuses was noted at 45 mg/kg/day. The no observed effect level (NOEL) for both the maternal animals and the F1 generation was 15 mg/kg/day (one quarter of the maximum human dose of 800 mg).

Imatinib was teratogenic in rats when administered during organogenesis at doses > 100 mg/kg, approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. These effects were not seen at doses ≤ 30 mg/kg.

No new target organs were identified in the rat juvenile development toxicology study (day 10 to 70 postpartum) with respect to the known target organs in adult rats. In the juvenile toxicology study, effects upon growth, delay in vaginal opening and preputial separation were observed at approximately 0.3 to 2 times the average paediatric exposure at the highest recommended dose of 340 mg/m2. In addition, mortality was observed in juvenile animals (around weaning phase) at approximately 2 times the average paediatric exposure at the highest recommended dose of 340 mg/m2.

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.

Papilloma/carcinoma of the preputial/clitoral gland were noted from 30 mg/kg/day onwards, representing approximately 0.5 or 0.3 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 times the daily exposure in children (based on AUC) at 340 mg/m2/day. The no observed effect level (NOEL) was 15 mg/kg/day. The renal adenoma/carcinoma, the urinary bladder and urethra papilloma, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumours of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day, representing approximately 1.7 or 1 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 1.2 times the daily exposure in children (based on AUC) at 340 mg/m2/day. The no observed effect level (NOEL) was 30 mg/kg/day.

The mechanism and relevance of these findings in the rat carcinogenicity study for humans are not yet clarified.

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.

The active substance imatinib demonstrates an environmental risk for sediment organisms.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: protein-tyrosine kinase inhibitor, ATC code: L01XE01

Mechanism of action

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

Pharmacodynamic effects

Imatinib is a protein-tyrosine kinase inhibitor which potently inhibits the Bcr-Abl tyrosine kinase at the in vitro, cellular and in vivo levels. The compound selectively inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia chromosome positive CML and acute lymphoblastic leukaemia (ALL) patients.

In vivo the compound shows anti-tumour 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), PDGF-R, 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 PDGF receptor 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 MDS/MPD, HES/CEL and DFSP. Imatinib inhibits signalling and proliferation of cells driven by dysregulated PDGFR and Abl kinase activity.

Clinical studies in chronic myeloid leukaemia

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, such as improvement in disease-related symptoms or increased survival.

Three large, international, open-label, non-controlled 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-alpha (IFN) therapy. One large, open-label, multicentre, international randomised phase III study has been conducted in patients with newly diagnosed Ph+ CML. In addition, children have been treated in two phase I studies and one phase II study.

In all clinical studies 38-40% of patients were > 60 years of age and 10-12% of patients were > 70 years of age.

Chronic phase, newly diagnosed: This phase III study in adult patients compared treatment with either single-agent Glivec or a combination of interferon-alpha (IFN) plus cytarabine (Ara-C). Patients showing lack of response (lack of complete haematological response (CHR) at 6 months, increasing 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 cross over 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 of 5 MIU/m2/day subcutaneously in combination with subcutaneous Ara-C 20 mg/m2/day for 10 days/month.

A total of 1,106 patients were randomised, 553 to each arm. Baseline characteristics were well balanced between the two arms. Median age was 51 years (range 18-70 years), with 21.9% of patients > 60 years of age. There were 59% males and 41% females; 89.9% caucasian and 4.7% black patients. Seven years after the last patient had been recruited, the median duration of first-line treatment was 82 and 8 months in the Glivec and IFN arms, respectively. The median duration of second-line treatment with Glivec was 64 months. Overall, in patients receiving first-line Glivec, the average daily dose delivered was 406 ± 76 mg. 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, 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 2.

Table 2 Response in newly diagnosed CML Study (84-month data)

Rates of complete haematological response, major cytogenetic response and complete cytogenetic response on first-line treatment were estimated using the Kaplan-Meier approach, for which non-responses were censored at the date of last examination. Using this approach, the estimated cumulative response rates for first-line treatment with Glivec improved from 12 months of therapy to 84 months of therapy as follows: CHR from 96.4% to 98.4% and CCyR from 69.5% to 87.2%, respectively.

With 7 years follow-up, there were 93 (16.8%) progression events in the Glivec arm: 37 (6.7%) involving progression to accelerated phase/blast crisis, 31 (5.6%) loss of MCyR, 15 (2.7%) loss of CHR or increase in WBC, and 10 (1.8%) CML unrelated deaths. In contrast, there were 165 (29.8%) events in the IFN+Ara-C arm, of which 130 occurred during first-line treatment with IFN+Ara-C.

The estimated rate of patients free of progression to accelerated phase or blast crisis at 84 months was significantly higher in the Glivec arm compared to the IFN arm (92.5% versus 85.1%, p<0.001). The annual rate of progression to accelerated phase or blast crisis decreased with time on therapy and was less than 1% annually in the fourth and fifth years. The estimated rate of progression-free survival at 84 months was 81.2% in the Glivec arm and 60.6% in the control arm (p<0.001). The yearly rates of progression of any type for Glivec also decreased over time.

A total of 71 (12.8%) and 85 (15.4%) patients died in the Glivec and IFN+Ara-C groups, respectively. At 84 months the estimated overall survival is 86.4% (83, 90) vs. 83.3% (80, 87) in the randomised Glivec and the IFN+Ara-C groups, respectively (p=0.073, log-rank test). This time-to-event endpoint is strongly affected by the high crossover rate from IFN+Ara-C to Glivec. The effect of Glivec treatment on survival in chronic phase, newly diagnosed CML has been further examined in a retrospective analysis of the above reported Glivec data with the primary data from another Phase III study using IFN+Ara-C (n=325) in an identical regimen. In this retrospective analysis, 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 and molecular response had a clear effect on long-term outcomes in patients on Glivec. Whereas an estimated 96% (93%) of patients with CCyR (PCyR) at 12 months were free of progression to accelerated phase/blast crisis at 84 months, only 81% of patients without MCyR at 12 months were free of progression to advanced CML at 84 months (p<0.001 overall, p=0.25 between CCyR and PCyR). For patients with reduction in Bcr-Abl transcripts of at least 3 logarithms at 12 months, the probability of remaining free from progression to accelerated phase/blast crisis was 99% at 84 months. Similar findings were found based on a 18-months landmark analysis.

In this study, dose escalations were allowed from 400 mg daily to 600 mg daily, then from 600 mg daily to 800 mg daily. After 42 months of follow-up, 11 patients 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 who did not escalate the dose, only one 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). The more frequent adverse reactions included gastrointestinal haemorrhages, conjunctivitis and elevation of transaminases or bilirubin. Other adverse reactions were reported with lower or equal frequency.

Chronic phase, Interferon failure: 532 adult patients were treated at a starting dose of 400 mg. The patients were distributed in three 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 to 35% Ph+ metaphases in the bone marrow).

In this study 65% of the patients achieved a major cytogenetic response that was complete in 53% (confirmed 43%) of patients (Table 3). A complete haematological response was achieved in 95% of patients.

Accelerated phase: 235 adult 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 (i.e. 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 (Table 3). Importantly, 27.7% of patients also achieved a major cytogenetic response, which was complete in 20.4% (confirmed 16%) 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.

Myeloid blast crisis: 260 patients with myeloid blast crisis were enrolled. 95 (37%) had received prior chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated 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=0.0220). The current estimate of the median survival of the previously untreated and treated patients was 7.7 and 4.7 months, respectively.

Lymphoid blast crisis: a limited number of patients were enrolled in phase I studies (n=10). The rate of haematological response was 70% with a duration of 2-3 months.

Table 3 Response in adult CML studies

Paediatric patients: A total of 26 paediatric patients of age < 18 years with either chronic phase CML (n=11) or CML in blast crisis or Ph+ acute leukaemias (n=15) were enrolled in a dose-escalation phase I trial. This was a population of heavily pretreated patients, as 46% had received prior BMT and 73% a prior multi-agent chemotherapy. Patients were treated at doses of Glivec 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 9 patients with chronic phase CML and cytogenetic data available, 4 (44%) and 3 (33%) achieved a complete and partial cytogenetic response, respectively, for a rate of MCyR of 77%.

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 induces a rapid response in newly diagnosed paediatric CML patients with a CHR of 78% after 8 weeks of therapy. The high rate of CHR is 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.

Clinical studies in Ph+ ALL

Newly diagnosed Ph+ ALL: In a controlled study (ADE10) of imatinib versus chemotherapy induction in 55 newly diagnosed patients aged 55 years and over, imatinib used as single agent induced a significantly higher rate of complete haematological response than chemotherapy (96.3% vs. 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 (see Table 4) after induction and the levels of bcr-abl transcripts were identical in the two 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 four uncontrolled clinical studies (AAU02, ADE04, AJP01 and AUS01) are consistent with the results described above. Imatinib in combination with chemotherapy induction (see Table 4) resulted in a complete haematological response rate of 93% (147 out of 158 evaluable patients) and in a 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). Disease-free survival (DFS) and overall survival (OS) constantly exceeded 1 year and were superior to historical control (DFS p<0.001; OS p<0.0001) in two studies (AJP01 and AUS01).

Table 4 Chemotherapy regimen used in combination with imatinib

Paediatric patients: In study I2301, a total of 93 paediatric, adolescent and young adult patients (from 1 to 22 years old) with Ph+ ALL were enrolled in an open-label, multicentre, sequential cohort, non-randomised phase III trial, and were treated with Glivec (340 mg/m2/day) in combination with intensive chemotherapy after induction therapy. Glivec was administered intermittently in cohorts 1-5, with increasing duration and earlier start of Glivec from cohort to cohort; cohort 1 receiving the lowest intensitiy and cohort 5 receiving the highest intensity of Glivec (longest duration in days with continuous daily Glivec dosing during the first chemotherapy treatment courses). Continuous daily exposure to Glivec early in the course of treatment in combination with chemotherapy in cohort 5-patients (n=50) improved the 4-year event-free survival (EFS) compared to historical controls (n=120), who received standard chemotherapy without Glivec (69.6% vs. 31.6%, respectively). The estimated 4-year OS in cohort 5-patients was 83.6% compared to 44.8% in the historical controls. 20 out of the 50 (40%) patients in cohort 5 received haematopoietic stem cell transplant.

Table 5 Chemotherapy regimen used in combination with imatinib in study I2301

Pharmacokinetic properties

Pharmacokinetics of Glivec

The pharmacokinetics of Glivec have been evaluated over a dosage range of 25 to 1,000 mg. Plasma pharmacokinetic profiles were analysed on day 1 and on either day 7 or day 28, by which time plasma concentrations had reached steady state.

Absorption

Mean absolute bioavailability for imatinib is 98%. There was high between-patient variability in plasma imatinib AUC levels 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 h), with a small reduction in AUC (7.4%) compared to fasting conditions. The effect of prior gastrointestinal surgery on drug absorption has not been investigated.

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 alpha-acid-glycoprotein, with little binding to lipoprotein.

Biotransformation

The main circulating metabolite in humans is the N-demethylated piperazine derivative, which shows similar in vitro potency to the parent. 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.

Imatinib and the N-demethyl metabolite together accounted for about 65% of the circulating radioactivity (AUC(0-48h)). The remaining circulating radioactivity consisted of a number of minor metabolites.

The in vitro results showed that CYP3A4 was the major human P450 enzyme catalysing the biotransformation of imatinib. Of a panel of potential comedications (acetaminophen, aciclovir, allopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, penicillin V) only erythromycin (IC50 50 µM) and fluconazole (IC50 118 µM) showed inhibition of imatinib metabolism which could have clinical relevance.

Imatinib was shown in vitro to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6 and CYP3A4/5. Ki values in human liver microsomes were 27, 7.5 and 7.9 μmol/l, respectively. Maximal plasma concentrations of imatinib in patients are 2-4 μmol/l, consequently an inhibition of CYP2D6 and/or CYP3A4/5-mediated metabolism of co-administered drugs is possible. Imatinib did not interfere with the biotransformation of 5-fluorouracil, but it inhibited paclitaxel metabolism as a result of competitive inhibition of CYP2C8 (Ki = 34.7 µM). This Ki value is far higher than the expected plasma levels of imatinib in patients, consequently no interaction is expected upon co-administration of either 5-fluorouracil or paclitaxel and imatinib.

Elimination

Based on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81% of the dose was recovered within 7 days in 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 h, suggesting that once-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose proportional in the range of 25-1,000 mg imatinib after oral administration. There was no change in the kinetics of imatinib on repeated dosing, and accumulation was 1.5-2.5-fold at steady state when dosed once daily.

Pharmacokinetics in GIST patients

In patients with GIST steady-state exposure was 1.5-fold higher than that observed for CML patients for the same dosage (400 mg daily). Based on preliminary population pharmacokinetic analysis in GIST patients, there were three variables (albumin, WBC and bilirubin) found to have a statistically significant relationship with imatinib pharmacokinetics. Decreased values of albumin caused a reduced clearance (CL/f); and higher levels of WBC led to a reduction of CL/f. However, these associations are not sufficiently pronounced to warrant dose adjustment. In this patient population, the presence of hepatic metastases could potentially lead to hepatic insufficiency and reduced metabolism.

Population pharmacokinetics

Based on population pharmacokinetic analysis in CML patients, there was a small effect of age on the volume of distribution (12% increase in patients > 65 years old). This change is not thought to be clinically significant. The effect of bodyweight on the clearance of imatinib is such that for a patient weighing 50 kg the mean clearance is expected to be 8.5 l/h, while for a patient weighing 100 kg the clearance will rise to 11.8 l/h. These changes are not considered sufficient to warrant dose adjustment based on kg bodyweight. There is no effect of gender on the kinetics of imatinib.

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/day achieved the same exposure, respectively, as doses of 400 mg and 600 mg in adult patients. The comparison of AUC(0-24) on day 8 and day 1 at the 340 mg/m2/day dose level revealed a 1.7-fold drug accumulation after repeated once-daily dosing.

Based on pooled population pharmacokinetic analysis in paediatric patients with haematological disorders (CML, Ph+ALL, or other haematological disorders treated with imatinib), clearance of imatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other demographics such as age, body weight and body mass index did not have clinically significant effects on the exposure of imatinib. The analysis confirmed that exposure of imatinib in paediatric patients receiving 260 mg/m2 once daily (not exceeding 400 mg once daily) or 340 mg/m2 once daily (not exceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or 600 mg once daily.

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.

Although the results of pharmacokinetic analysis showed that there is considerable inter-subject 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.

Date of revision of the text

22 March 2018

Marketing authorisation holder

Novartis Europharm Limited

Frimley Business Park

Camberley GU16 7SR

United Kingdom

Special precautions for storage

Do not store above 30°C.

Store in the original package in order to protect from moisture.

Nature and contents of container

Glivec 100 mg film-coated tablets

PVC/alu blisters

Packs containing 20, 60, 120 or 180 film-coated tablets

Glivec 400 mg film-coated tablets

PVDC/alu blisters

Packs containing 10, 30 or 90 film-coated tablets

Not all pack sizes may be marketed.

Marketing authorisation number(s)

Glivec 100 mg film-coated tablets

EU/1/01/198/007

EU/1/01/198/008

EU/1/01/198/011

EU/1/01/198/012

Glivec 400 mg film-coated tablets

EU/1/01/198/009

EU/1/01/198/010

EU/1/01/198/013

Special precautions for disposal and other handling

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

Date of first authorisation/renewal of the authorisation

Date of first authorisation: 07 November 2001

Date of latest renewal: 07 November 2006