Imatinib mesylate, an inhibitor of Bcr-Abl tyrosine kinase, is an antineoplastic agent.1, 50
Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia
Imatinib is used for the treatment of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) in adult and pediatric patients.1, 50 Imatinib is designated an orphan drug by FDA for use in this condition.4
First-line Therapy for Chronic Phase CML
Imatinib is used for the first-line treatment of chronic phase Ph+ CML in adult patients.1, 50
The indication for this use is based on the results of an open-label, multicenter, randomized phase 3 trial in 1,106 patients receiving either imatinib or combination therapy with interferon alfa and cytarabine for newly diagnosed chronic phase Ph+ CML.1, 16, 22, 23 Single-agent therapy consisted of imatinib at an initial dose of 400 mg daily with dose escalations to 600 mg daily and 800 mg daily as tolerated.1 Combination therapy consisted of interferon alfa 5 million units/m2 given subcutaneously daily with cytarabine 20 mg/m2 given subcutaneously daily for 10 days every month.1 Crossover therapy was permitted if treatment failure or unacceptable toxicity occurred.1 The patients were mostly Caucasian (59% males and 41% females) with a median age of 51 years.1
At the time of data cut-off, the median duration of first-line therapy with imatinib or combination therapy with interferon alfa and cytarabine was 82 or 8 months, respectively.1 The primary efficacy endpoint was progression-free survival, and progression was defined as death, progression to accelerated phase or blast phase CML, loss of complete hematologic response, loss of major cytogenetic response, or increasing WBC count in patients who did not achieve complete hematologic response.1 According to the intention-to-treat analysis, the estimated rate of progression-free survival at 84 months was higher in patients receiving imatinib (81.2%) than in those receiving interferon alfa and cytarabine (60.6%).1 The estimated rate of patients free of progression to accelerated phase CML or blast crisis at 84 months was higher in patients receiving imatinib (92.5%) than in those receiving interferon alfa and cytarabine (85.1%); however, no statistically significant difference in overall survival was observed (hazard ratio: 0.75 with 95% confidence interval of 0.547-1.028).1
In patients who achieved complete cytogenetic response and major molecular response (a reduction of at least 3 logarithms in the amount of Bcr-Abl transcripts measured by quantitative reverse transcriptase polymerase chain reaction) at 12 months, the probability of remaining progression free at 60 months was 95%.1 In patients who achieved complete cytogenetic response, but not major molecular response, the probability of remaining progression free at 60 months was 89% and for those who did not achieve complete cytogenetic response, the probability was 70%.1 Secondary endpoints, including complete hematologic response and major cytogenetic response, were higher in patients receiving imatinib than in those receiving interferon alfa and cytarabine.1
Imatinib mesylate is used for the treatment of Ph+ CML in patients who are in blast crisis, in the accelerated phase, or in the chronic phase of the disease after failure of interferon alfa therapy.1, 10, 50
The current indication of imatinib is based principally on the results of 3 international, open-label, single-arm studies in more than 1000 patients with Ph+ CML.1 The first study enrolled patients in the chronic phase of CML previously treated with interferon alfa therapy (i.e., inadequate hematologic response following 6 months of treatment, inadequate cytogenetic response following 1 year of treatment, hematologic or cytogenetic relapse, or intolerance to interferon).1, 8, 28, 29 The second study enrolled patients who were in the accelerated phase of CML, while the third study enrolled patients in myeloid blast crisis.1, 30, 31 Patients chronic phase of CML previously treated with interferon alfa received an initial imatinib dosage of 400 mg daily (increased to 600 mg daily as necessary), while those in accelerated phase or blast crisis received either 400 or 600 mg of the drug daily.1, 8 The median duration of therapy with imatinib in patients in chronic phase, accelerated phase, or blast crisis was 29, 18, or 4 months, respectively.1 Among 532 patients with chronic phase CML following failure of interferon alfa therapy, hematologic response rate was 95% and major cytogenetic response rate was 60%.1 Among 235 patients with CML in accelerated phase, hematologic response rate was 71% and major cytogenetic response rate was 21%.1 Among 260 patients in myeloid blast crisis, hematologic response rate was 31% and major cytogenetic response was 7%.1
Hematologic response (i.e., complete hematologic response and, in patients in accelerated phase or blast crisis, no evidence of leukemia or return to chronic phase of CML) was reported in 95, 71, or 31% of patients in the chronic phase, accelerated phase, or blast crisis, respectively; complete hematologic response was achieved in approximately 95, 38, or 7% of these patients, respectively.1 Major cytogenetic response (i.e., complete or partial suppression of Ph+ cells) occurred in 60, 21, or 7% of patients in the chronic phase, accelerated phase, or blast crisis, respectively, while complete cytogenetic response (i.e., no Ph+ cells in metaphase) was achieved in 39, 16, or 2% of these patients, respectively.1 The rates of hematologic response and major cytogenetic response were higher in patients in accelerated phase or blast crisis who received an initial dosage of 600 mg of imatinib daily compared with those who received an initial dosage of 400 mg daily.1
Median time to hematologic response in patients receiving imatinib was 1 month;1, 10 median duration of hematologic response was 10 months in patients in blast crisis and 29 months in those with accelerated phase CML receiving an initial dosage of imatinib 600 mg daily.1 About 88% of patients with late chronic phase CML and 64% of patients with accelerated phase CML maintained major cytogenetic response for 2 years.1 About 27% of patients with blast crisis who achieved an initial hematologic response to imatinib therapy maintained hematologic response for 2 years.1 In patients with late chronic phase CML who received imatinib therapy for 2 years, the estimated overall survival was 91%.1 In patients with accelerated CML, median survival was 21 months in patients receiving an initial imatinib dosage of 400 mg daily; median survival had not been reached in those receiving an initial imatinib dosage of 600 mg daily.1 In patients with blast crisis, median survival was 7 months.1
Resistance to imatinib, particularly in patients with advanced stage CML, has developed during therapy with the drug.6, 11 In patients with myeloid blast crisis, development of imatinib resistance was observed as early as 42 days following initiation of therapy.6 Resistance to imatinib has not been evaluated in all patient groups;8 however, limited data from several open-label studies indicate a relapse rate of 4 or 43-80% in patients in chronic phase or blast crisis, respectively.5, 6, 8, 11 Although the mechanism(s) of resistance to imatinib has not been fully determined to date, mutation and/or amplification of the Bcr-Abl gene (resulting in increased expression of Bcr-Abl tyrosine kinase) may be associated with decreased efficacy of the drug.8, 11, 12, 13, 14
First-line Therapy for Chronic Phase CML
Imatinib is used for the first-line treatment of chronic phase Ph+ CML in pediatric patients.1, 50
Efficacy and safety for this indication are based on the results of an open-label, uncontrolled phase 2 trial in 51 pediatric patients receiving imatinib 340 mg/m2 daily for newly diagnosed chronic phase Ph+ CML.1, 27 After 8 weeks of imatinib therapy, complete hematologic response was observed in 78% of patients.1 The complete cytogenetic response rate (typically achieved between months 3 and 10) was 65%, which is comparable to the rate observed in adult patients; the majority of these patients achieved a complete cytogenetic response between month 3 and 10 with an estimated median time to response of 6.74 months.1 Patients were allowed to withdraw from protocol therapy to undergo alternative therapy, including hematopoietic stem cell transplantation; 31 children withdrew from protocol therapy and underwent stem cell transplantation.1 Among 25 patients who withdrew from protocol therapy to undergo stem cell transplantation following a median of 9 treatment cycles, 52 or 20% achieved complete or partial cytogenetic response, respectively.1
Second-line Therapy for Chronic Phase CML
Imatinib is used for the second-line treatment of pediatric patients with chronic phase Ph+ CML that has recurred following stem cell transplantation or is resistant to interferon alfa therapy.1, 50
The indication for this use is based on the results of 2 small uncontrolled studies in pediatric patients receiving imatinib as second-line therapy for chronic phase CML.1 In the first study, which involved 14 pediatric patients ranging in age from 3 to 20 years of age, a complete cytogenetic response was observed in 7 patients.1 In the second study, which involved 3 patients, a complete cytogenetic response was observed in 2 patients.1
Adult Patients: Chronic Phase CML
Guidelines recommend bosutinib, dasatinib, imatinib, or nilotinib for the first-line treatment of newly diagnosed chronic phase CML; selection of the tyrosine kinase inhibitor (TKI) should be based on risk score, toxicity profile, patient's age, ability to tolerate therapy, and presence of comorbid conditions.36 All of these TKIs are appropriate first-line options for patients with chronic phase CML across all risk scores.36 In patients with an intermediate- or high-risk score, disease progression to accelerated or blast phase CML occurs more frequently; bosutinib, dasatinib, and nilotinib are associated with a reduced risk of disease progression than imatinib and are preferred for patients with an intermediate- or high-risk score.36
Philadelphia Chromosome-Positive Acute Lymphocytic Leukemia
Imatinib is used for the treatment of Ph+ acute lymphocytic (lymphoblastic) leukemia (ALL) in adults following failure (secondary to resistance or intolerance) of prior therapy; the drug also is used in combination with chemotherapy for the treatment of pediatric patients at least 1 year of age with newly diagnosed Ph+ ALL.1, 50 Imatinib is designated an orphan drug by FDA for use in this condition.4
Relapsed or Refractory Ph+ ALL
Imatinib is used for the treatment of adult patients with relapsed or refractory Ph+ ALL.1 Safety and efficacy of imatinib for the treatment of ALL is based on 43 patients with relapsed or refractory Ph+ ALL who received imatinib 600 mg daily in a phase 2 or study.1 Complete hematologic response was achieved in 19% of patients.1 Complete cytogenetic response and major cytogenetic response was achieved in 35 and 21%, respectively, of patients.1 No evidence of leukemia was observed in 12% of patients.1
Imatinib is used in combination with chemotherapy for the treatment of newly diagnosed Ph+ ALL in pediatric patients.1 Safety and efficacy of imatinib for the treatment of newly diagnosed Ph+ ALL in pediatric patients is based principally on a multicenter, nonrandomized pilot study in pediatric and young adult patients with very high-risk ALL (defined as those with an expected 5-year event-free survival of less than 45%).1, 32 Patients were enrolled in the study following induction therapy.1
Pediatric patients in the Ph+ ALL cohort who had an appropriate HLA-matched family donor received a minimum of 2 cycles of consolidation therapy followed by imatinib 340 mg/m2 per day in combination with intensive chemotherapy and hematopoietic stem cell transplantation.1 The median age of 92 patients with Ph+ ALL was 9.5 years (range of 1-21 years).1 In 5 successive cohorts of patients, imatinib exposure was systematically increased by earlier introduction and prolonged duration.1 Cohort 1 received the lowest intensity and cohort 5 received the highest intensity of imatinib exposure.1 Among 50 patients with Ph+ ALL in cohort 5, 30 patients received chemotherapy and imatinib and 20 patients received chemotherapy and imatinib therapy followed by hematopoietic stem cell transplantation and imatinib maintenance therapy.1 Patients in cohort 5 received chemotherapy and imatinib continuously beginning on cycle 1 of post-induction chemotherapy; imatinib was continued through cycles 1-4 of maintenance therapy.1 During cycles 5-12 of maintenance therapy, imatinib was administered for 28 days of a 56-day treatment cycle.1 Patients who underwent hematopoietic stem cell transplantation received 42 days of imatinib prior to transplantation, and 28 weeks (196 days) of imatinib after the immediate post-transplant period.1 At a median follow-up duration of 40.5 months, the estimated 4-year event-free survival was 70%.1
Efficacy of imatinib also was evaluated in a phase 3, open-label trial in 189 pediatric patients with Ph+ ALL.33 In this study, patients were randomized to receive imatinib or dasatinib as soon as diagnosis was made, usually on day 8 of remission induction.33 In this study, the median age of patients was 7.8 years (range of 5.2-11.3 years).33 Both 4-year event-free survival and overall survival rates were higher in patients receiving dasatinib compared with those receiving imatinib.33
Adult Patients: Relapsed or Refractory Ph+ ALL
Although there is no universally accepted treatment protocol for the treatment of relapsed or refractory ALL and evidence based on randomised, controlled trials is lacking, there is consensus on the general approach to managing patients with relapsed or refractory ALL.1 Some experts recommend prolonged monitoring of Bcr-Abl transcript levels and resistance mutation screening in patients with persistent minimal residual disease or re-increasing minimal residual disease level; therapy with a second- or third-generation tyrosine kinase inhibitor should be offered to high risk patients with Ph+ ALL.37 Patients with imatinib-refractory Ph+ ALL may respond to nilotinib or dasatinib while patients with T315I Bcr-Abl mutation-positive Ph+ ALL may respond to ponatinib therapy.37 Tyrosine kinase inhibitors have been shown to have a more favorable toxicity profile in elderly patients compared to repeated cycles of conventional myelosuppressive chemotherapy.37 Long-term survival has not been demonstrated with tyrosine kinase inhibitor therapy post-relapse; the majority of patients undergo allogeneic stem cell transplantation.37
Myelodysplastic/Myeloproliferative Diseases
Imatinib is used for the treatment of adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor ( PDGFR ) gene rearrangements.1, 50 Imatinib is designated an orphan drug by FDA for use in this condition.4
Efficacy and safety of imatinib in patients with MDS/MPD is based principally on the results of an open-label, multicenter, phase 2 trial in patients with life-threatening diseases associated with Abl, c-Kit, or PDGFR protein tyrosine kinases.1 Seven patients with MDS/MPD received imatinib 400 mg daily.1 The age range of the 7 patients enrolled in this study was 20-86 years.1 The primary efficacy analysis also included published case reports and a clinical study of 24 patients with MDS/MPD between 2-79 years of a most of these patients received imatinib 400 mg daily.1 In a pooled analysis of the 31 patients, complete hematologic response was reported in 45% of patients and major cytogenetic response was achieved in 39%.1 Among 16 patients with PDFGR gene rearrangement, 13 patients achieved complete hematologic response.1 Among 12 patients with PDGFR gene rearrangement evaluated for cytogenetic response, 10 patients achieved complete cytogenetic response.1 Among 14 patients without a chromosome translocation associated with PDGFR gene rearrangement, 1 patient achieved complete hematologic response.1
Imatinib is used for the treatment of adult patients with aggressive systemic mastocytosis (ASM) with unknown c-Kit mutation status or absence of a c-Kit D816V mutation.1, 50 Imatinib is designated an orphan drug by FDA for use in this condition.4
Efficacy and safety of imatinib in patients with ASM are based principally on the results of an open-label, multicenter, phase 2 trial in patients with life-threatening diseases associated with Abl, c-Kit, or PDGFR protein tyrosine kinases.1 Five patients with ASM were treated with imatinib 100-400 mg daily.1 The age range of the 5 patients enrolled in this study was 49-74 years.1 The primary efficacy analysis also included published literature and case reports of 23 patients with ASM who received imatinib 100-400 mg daily.1 In a combined analysis of the 28 patients, complete hematologic response was reported in 29% of patients.1 All 7 patients with FIP1L1-PDGFR fusion kinase positive status achieved complete hematologic response while only 25% of those with a D816V mutation achieved a complete hematologic response.1
Imatinib has not been shown to be effective in patients with less aggressive forms of systemic mastocytosis (SM); therefore, the manufacturer does not recommend imatinib for the treatment of cutaneous mastocytosis, indolent systemic mastocytosis (smoldering SM or isolated bone marrow mastocytosis), SM with an associated clonal hematological nonmast cell lineage disease, mast cell leukemia, mast cell sarcoma or extracutaneous mastocytoma.1
Patients with SM harboring a c-Kit D816V mutation are not sensitive to imatinib; the manufacturer states that such patients should not receive imatinib.1
Hypereosinophilic Syndrome and/or Chronic Eosinophilic Leukemia
Imatinib is used for the treatment of adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have FIP1L1-PDGFR fusion kinase (as detected by mutational analysis or CHIC2 allele deletion on FISH); the drug also is used in patients with HES and/or CEL with unknown or negative FIP1L1-PDGFR fusion kinase status.1, 50 Imatinib is designated an orphan drug by FDA for use in this condition.4
Efficacy and safety of imatinib in patients with HES/CEL are based principally on the results of an open-label, multicenter, phase 2 trial in patients with life-threatening diseases associated with Abl, c-Kit, or PDGFR protein tyrosine kinases.1 Fourteen patients with HES/CEL were treated with imatinib 100 mg to 1 g daily.1 The age range of the 14 patients enrolled in this study was 16-64 years.1 The primary efficacy analysis also included published case reports and case series of 162 patients with HES/CEL who received imatinib 75-800 mg daily.1 In a combined analysis of the 176 patients, complete hematologic response was reported in 61% of patients.1 All 61 patients with FIP1L1-PDGFR fusion kinase positive status achieved complete hematologic response.1
Imatinib is used for the treatment of adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.1, 50 Imatinib is designated an orphan drug by FDA for use in this condition.4
Efficacy and safety of imatinib in patients with dermatofibrosarcoma protuberans are based principally on the results of an open-label, multicenter, phase 2 trial in patients with severe diseases associated with Abl, c-Kit, or PDGFR protein tyrosine kinases.1 Twelve patients with dermatofibrosarcoma protuberans were treated with imatinib 800 mg daily.1 The age range of the 12 patients enrolled in this study was 23-75 years.1 The primary efficacy analysis also included published case reports of 6 patients with dermatofibrosarcoma protuberans who received varying dosages of imatinib.1 In a combined analysis of the 18 patients, complete response was achieved in 39% of patients.1 Among 10 patients with PDGF- gene rearrangement, 4 patients achieved complete responses.1 The median duration of response in the phase 2 study was 6.2 months, with a maximum duration of 24.3 months, while the duration of response was 4 weeks to more than 20 months in published literature.1
Gastrointestinal Stromal Tumors
Imatinib is used for the adjuvant treatment of c-Kit (CD117) positive gastrointestinal stromal tumors (GIST) following complete resection in adults.1, 50 Imatinib is designated an orphan drug by FDA for use in this condition.4 The indication for this use is based on the results of 2 multicenter, randomized studies.1, 39, 40
In a multicenter, double-blind, placebo-controlled, randomized study, 713 patients were randomized to receive imatinib 400 mg daily or placebo for 12 months.1 Patients were included in the study if they had a histologic diagnosis of primary GIST expressing c-Kit protein by immunochemistry and complete gross resection (tumor size ≥3 cm in maximum dimension) 14-70 days prior to study enrollment.1 At median follow-up duration of 15 months in patients without a recurrence-free survival event, the risk of recurrence or death from any cause was decreased by 61%.1 After the interim analysis, 72 of 354 patients initially randomized to placebo crossed over to the imatinib treatment group.1 In an updated analysis at a median follow-up duration of 50 months, the risk of recurrence or death was decreased by 28%.1 At a median follow-up duration of 61 months, the risk of death was decreased by 19%; however, statistical significance was not reached.1
In another randomized, multicenter, open-label, phase 3 trial, imatinib 400 mg daily was evaluated in 397 adult patients with c-Kit (CD117) positive GIST following surgical resection.1 At a median follow-up duration of 42 months in patients without a recurrence-free survival event, imatinib therapy for a duration of 36 months significantly prolonged recurrence-free survival compared with 12 months of therapy (hazard ratio 0.46).1 At a median follow-up duration of 48 months for living patients, imatinib therapy for a duration of 36 months significantly prolonged overall survival compared 12 months of therapy (hazard ratio 0.45).1
Imatinib is used for the treatment of malignant GIST in patients with unresectable tumor or metastatic disease that is c-Kit (CD117) positive.1, 50 This indication is based on objective response rate; there currently are no controlled trials demonstrating a clinical benefit (e.g., reduced disease-related symptoms, increased survival).1
Efficacy and safety of this indication are based on the results of 2 open-label, multinational, phase 3 studies and a phase 2 study.1, 19, 35, 38
In the phase 3 studies, 1640 patients received either imatinib 400 mg daily or imatinib 800 mg daily continuously until disease progression or unacceptable toxicity occurred.1 Patients randomized to imatinib 400 mg daily were permitted to crossover to receive imatinib 800 mg daily upon disease progression.1 All patients enrolled in the studies had c-Kit (CD117) positive unresectable and/or metastatic malignant GIST.1 At a combined median follow-up duration of 37.5 months, median progression-free survival was 18.9 or 23.2 months in patients receiving imatinib 400 or 800 mg daily, respectively.1 No difference in overall survival was observed between the treatment groups.1
In the phase 2 study, 147 patients received either imatinib 400 or 600 mg daily for up to 36 months for unresectable or metastatic malignant GIST.1, 19 The objective response rate was 68.5 or 67.6% in patients who received imatinib 400 mg daily or 600 mg daily, respectively.1 The median time to response was 12 weeks and the estimated median duration of response was 118 weeks.1 The study was not designed with adequate power to detect a statistically significant difference in response rates between the dose groups.1, 19
Imatinib has also been evaluated for the treatment of bone cancer†, 41, 42, 43 desmoid tumors†, 45, 46 AIDS-related Kaposi sarcoma†, 47 melanoma†, 48, 49 pigmented villonodular synovitis/tenosynovial giant cell tumor†.44
Dispensing and Administration Precautions
Imatinib is available as tablets (Gleevec®) and an oral solution (Imkeldi®).1, 50
In adults, an imatinib dosage of 400 or 600 mg should be administered once daily and a dosage of 800 mg daily should be administered as 400 mg twice daily.1, 50 For daily dosing of 800 mg and above of the imatinib tablet, dosing should be accomplished using the 400-mg tablet to reduce exposure to iron.1
In children or adolescents, imatinib may be given as a once-daily dose or, alternatively, divide the daily dose equally in the morning and the evening.1, 50
Administer imatinib mesylate with a meal and a large glass of water to minimize gastric irritation.1, 50 Alternatively, for patients unable to swallow tablets, imatinib tablets may be dispersed in a glass of water or apple juice.1 The required number of tablets should be dispersed in 50 mL of beverage for each 100-mg tablet or 200 mL of beverage for each 400-mg tablet.1 Administer suspension immediately after complete disintegration of the tablet(s).1
Imatinib oral solution should be measured with an accurate measuring device, not a household teaspoon.50 Patients should ask a pharmacist for a press-in bottle adapter and oral dispensing syringe for measuring a correct dose of the oral solution.50 Doses of the solution may be rounded to the nearest measurable graduation mark on the oral syringe, if necessary.50
The manufacturer states that imatinib therapy may be continued as indicated in the absence of progressive disease or unacceptable toxicity.1, 50
If a dose of imatinib is missed, the prescribed dose should be taken at the next scheduled time; an additional dose should not be administered to replace the missed dose.1, 50
Store imatinib capsules and oral solution at 20-25ºC; excursions between 15-30ºC are permitted.1, 50 The imatinib oral solution should be stored and dispensed in the original container only; any open bottle should be discarded after 30 days.50
Dosage of imatinib mesylate is expressed in terms of imatinib.1
First- or second-line treatment of Ph+ chronic phase CML : The recommended initial adult dosage of imatinib for the first-line treatment of Ph+ chronic phase CML is 400 mg daily.1, 50 If there is inadequate hematologic response after at least 3 months of therapy, failure to achieve a cytogenetic response after 6-12 months of therapy, loss of a previously achieved hematologic or cytogenetic response, or evidence of disease progression, the manufacturer states that, in the absence of severe adverse drug or hematologic effects, adult dosage of imatinib may be increased to 600 mg daily.1, 50
Second-line treatment of Ph+ CML in accelerated phase or blast crisis : The recommended adult dosage of imatinib for the second-line treatment of Ph+ CML in accelerated phase or blast crisis is 600 mg daily.1, 50 If there is inadequate hematologic response after at least 3 months of therapy, failure to achieve a cytogenetic response after 6-12 months of therapy, loss of a previously achieved hematologic or cytogenetic response, or evidence of disease progression, the manufacturer states that, in the absence of severe adverse drug or hematologic effects, adult dosage of imatinib may be increased to 800 mg daily (administered as 400 mg twice daily).1, 50
The recommended pediatric dosage of imatinib for the first-line treatment of Ph+ chronic phase CML is 340 mg/m2 daily; the daily dose should not exceed 600 mg.1, 50 Imatinib may be administered as a once-daily dose or twice-daily in 2 equally divided doses.1, 50
Safety and efficacy of imatinib therapy have not been established in pediatric patients less than 1 year of age with Ph+ chronic phase CML.1, 50
For the treatment of relapsed or refractory Ph+ ALL, the recommended adult dosage of imatinib is 600 mg daily.1, 50
For the treatment of newly diagnosed Ph+ ALL in combination with chemotherapy in children 1 year of age or older, the recommended pediatric dosage of imatinib is 340 mg/m2 daily; the daily dose should not exceed 600 mg.1, 50 Imatinib may be administered as a once-daily dose.1, 50
Myelodysplastic Syndrome/Myeloproliferative Diseases
For the treatment of myelodysplastic syndrome or myeloproliferative disease associated with gene rearrangements of PDGFR , the recommended adult dosage of imatinib is 400 mg daily.1, 50
Aggressive Systemic Mastocytosis
For the treatment of aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation, the recommended adult dosage of imatinib is 400 mg daily.1, 50 For ASM with unknown status of the D816V c-Kit mutation that is not responding satisfactorily to other therapies, treatment with an adult imatinib dosage of 400 mg daily may be considered.1, 50 For ASM without the D816V c-Kit mutation or of unknown D816V c-Kit mutational status that is associated with eosinophilia (a clonal hematologic disease related to the FIP1L1-PDGFR fusion kinase), the recommended initial adult dosage of imatinib is 100 mg daily; if therapeutic response is insufficient, the dosage may be escalated from 100 mg to 400 mg as tolerated.1, 50
Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia
For the treatment of hypereosinophilic syndrome (HES) or chronic eosinophilic leukemia (CEL) in patients without FIP1L1-PDGFR fusion kinase expression or in patients in whom expression of FIP1L1-PDGFR fusion kinase is unknown, the recommended adult dosage of imatinib is 400 mg daily.1, 50 For HES or CEL with FIP1L1-PDGFR fusion kinase expression, the recommended initial adult dosage of imatinib is 100 mg daily; if therapeutic response is insufficient, the dosage may be escalated from 100 to 400 mg as tolerated.1, 50
Dermatofibrosarcoma Protuberans
For unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans, the recommended adult dosage of imatinib is 800 mg daily.1, 50
Gastrointestinal Stromal Tumors
Unresectable and/or metastatic malignant GIST : The recommended adult dosage of imatinib is 400 mg daily for the treatment of unresectable and/or metastatic malignant GIST; if therapeutic response is insufficient, the dosage may be increased to 800 mg daily as tolerated.1, 50
Adjuvant therapy : The recommended adult dosage of imatinib is 400 mg daily for the adjuvant treatment of GIST following complete gross resection.1, 50 The optimal treatment duration with imatinib is unknown.1, 50
Dosage Modification for Toxicity
Adults : In patients who exhibit substantial increases in bilirubin (>3 times the upper limit of normal [ULN]) or aminotransferase concentrations (>5 times the ULN), the manufacturer recommends withholding imatinib therapy until bilirubin concentrations decrease to <1.5 times the ULN and aminotransferase concentrations decrease to <2.5 times the ULN.1, 50 Imatinib therapy may then be resumed at a reduced daily dosage (e.g., 400 mg to 300 mg, 600 mg to 400 mg, or 800 mg to 600 mg).1, 50
Pediatric patients : In pediatric patients who exhibit substantial increases in bilirubin (>3 times the ULN) or hepatic aminotransferase concentrations (>5 times the ULN), the manufacturer recommends that therapy with imatinib be withheld until bilirubin concentrations decrease to <1.5 times the ULN or aminotransferase concentrations decrease to <2.5 times the ULN.1, 50 Imatinib therapy may then be resumed at a dosage reduced from 340 mg/m2 daily to 260 mg/m2 daily.1, 50
If hematologic toxicity occurs, dosing interruption, dosage reduction, or discontinuance of imatinib therapy may be necessary in adults (see Table 1) and pediatric patients (see Table 2).1
Use (Initial Dosage) | Hematologic Measurements | Dosage Modification |
|---|---|---|
Aggressive systemic mastocytosis (initial starting dosage = 400 mg daily) | ANC <1000/mm3 and/or platelets <50,000/mm3 | First occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at original starting dosage (400 mg daily)1 |
Second occurrence: Withhold therapy until ANC ≥1500/mm3 and/or platelet count ≥75,000/mm3, then resume at a reduced dosage of 300 mg daily1 | ||
Aggressive systemic mastocytosis associated with eosinophilia (initial starting dosage = 100 mg daily) | ANC <1000/mm3 and/or platelets <50,000/mm3 | Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, resume at same dosage1 |
Hypereosinophilic syndrome/chronic eosinophilic leukemia without FIP1L1-PDGFR fusion kinase expression or unknown FIP1L1-PDGFR status (initial starting dosage = 400 mg) | ANC <1000/mm3 and/or platelets <50,000/mm3 | First occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at original starting dosage (400 mg daily)1 |
Second occurrence: Withhold therapy until ANC ≥1500/mm3 and/or platelet count ≥75,000/mm3, then resume at a reduced dosage of 300 mg daily1 | ||
Hypereosinophilic syndrome/chronic eosinophilic leukemia with FIP1L1-PDGFR fusion kinase (initial starting dosage = 100 mg daily) | ANC <1000/mm3 and/or platelets <50,000/mm3 | Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, resume at same dosage1 |
Chronic phase CML (initial starting dosage = 400 mg daily) | ANC <1000/mm3 and/or platelets <50,000/mm3 | First occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at original starting dosage (400 mg daily)1 |
Second occurrence: Withhold therapy until ANC ≥1500/mm3 and/or platelet count ≥75,000/mm3, then resume at a reduced dosage of 300 mg daily1 | ||
Myelodysplastic Syndrome/Myeloproliferative Diseases (initial starting dosage = 400 mg daily) | ANC <1000/mm3 and/or platelets <50,000/mm3 | First occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at original starting dosage (400 mg daily)1 |
Second occurrence: Withhold therapy until ANC ≥1500/mm3 and/or platelet count ≥75,000/mm3, then resume at a reduced dosage of 300 mg daily1 | ||
GIST (initial starting dosage = 400 mg daily) | ANC <1000/mm3 and/or platelets <50,000/mm3 | First occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at original starting dosage (400 mg daily)1 |
Second occurrence: Withhold therapy until ANC ≥1500/mm3 and/or platelet count ≥75,000/mm3, then resume at a reduced dosage of 300 mg daily1 | ||
Ph+ CML in accelerated phase or blast crisis (initial starting dosage = 600 mg daily) | ANC <500/mm3 and/or platelets <10,000/mm3 and unrelated to CML | Reduce dosage to 400 mg daily1 |
If cytopenia persists for 2 weeks, further reduce dosage to 300 mg daily1 | ||
If cytopenia persists for 4 weeks, withhold subsequent doses until ANC ≥1000/mm3 and platelet counts ≥20,000/mm3, then resume therapy at a reduced dosage of 300 mg daily1 | ||
Ph+ ALL (initial starting dosage = 600 mg daily) | ANC <500/mm3 and/or platelets <10,000/mm3 and unrelated to ALL | Reduce dosage to 400 mg daily1 |
If cytopenia persists for 2 weeks, reduce dosage further to 300 mg daily1 | ||
If cytopenia persists for 4 weeks, withhold subsequent doses until ANC ≥1000/mm3 and platelet counts ≥20,000/mm3, then resume therapy at a reduced dosage of 300 mg daily1 | ||
Dermatofibrosarcoma Protuberans (initial starting dosage = 800 mg daily) | ANC <1000/mm3 and/or platelets <50,000/mm3 | First occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume therapy at a reduced dosage of 600 mg1 |
Second occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at a reduced dosage of 400 mg daily1 |
Use | Absolute Neutrophil Count (ANC) and/or Platelet Count | Dosage Modification |
|---|---|---|
Newly diagnosed chronic phase CML (initial starting dosage = 340 mg/m2) | ANC <1000/mm3 and/or platelets <50,000/mm3 | First occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at same dosage1 |
Second occurrence: Withhold therapy until ANC ≥1500/mm3 and platelet count ≥75,000/mm3, then resume at a reduced dosage of 260 mg/m21 |
If severe nonhematologic toxicity (e.g., severe fluid retention) develops, withhold therapy until the toxicity resolves, then resume therapy as appropriate.1, 50
Concomitant Use of Drugs Affecting Hepatic Microsomal Enzymes
Avoid concomitant use with strong CYP3A4 inducers.1, 50 If concomitant use of a strong CYP3A4 inducer cannot be avoided, the manufacturer recommends increasing the imatinib dosage by at least 50%.1, 50 Carefully monitor clinical response.1, 50
In patients with mild to moderate hepatic impairment, no dosage adjustment is necessary.1, 50
In patients with severe hepatic impairment, the manufacturer recommends reducing the dosage by 25%.1, 50
In patients with mild renal impairment (creatinine clearance 40-59 mL/minute), the daily dosage should not exceed 600 mg.1, 50
In patients with moderate renal impairment (creatinine clearance 20-39 mL/minute), decrease initial dosage by 50%; subsequent dosage may be increased as tolerated up to a maximum dosage of 400 mg.1, 50
In patients with severe renal impairment, use imatinib with caution.1, 50 An imatinib dosage of 100 mg daily has been tolerated in 2 patients with severe renal impairment.1, 50
The manufacturer makes no specific dosage recommendations for geriatric patients.1, 50
Edema, occasionally serious, may occur in patients receiving imatinib.1 The risk of edema was increased in patients older than 65 years of age and those receiving higher imatinib dosages.1 Severe superficial edema was reported in 1.5% of patients with newly diagnosed CML and in 2-6% of other adult patients with CML.1 Other types of severe fluid retention were reported (e.g., pleural effusion, pericardial effusion, pulmonary edema, ascites) in imatinib-treated patients with newly diagnosed CML (1.3%), and in other adult patients with CML (2-6%).1 In patients with GIST, severe fluid retention was reported in 9-13% of imatinib-treated patients.1 In a randomized trial, severe (grade 3 or 4) fluid retention occurred in 2.5% of patients with newly diagnosed Ph+ chronic phase CML receiving imatinib and in 3.9% of patients receiving nilotinib 300 mg twice daily.1 Effusions (i.e., pleural effusion, pericardial effusion, ascites) or pulmonary edema have been observed in 2.1% of patients receiving imatinib and in 2.2% of those receiving nilotinib 300 mg twice daily.1
Monitor signs (e.g., body weight) and symptoms of fluid retention regularly during imatinib therapy; provide appropriate treatment as necessary.1, 50
Cytopenias, including neutropenia, thrombocytopenia, and anemia, have occurred in patients receiving imatinib.1, 50 In patients with CML, the frequency of cytopenias is dependent on the stage of disease (higher incidence in patients with accelerated phase or blast crisis CML).1 In pediatric patients receiving imatinib for the treatment of CML, grade 3 or 4 neutropenia, thrombocytopenia, and anemia were the most common toxicities.1 Monitor complete blood cell counts (CBCs) weekly during the first month of therapy, every other week during the second month, and periodically (e.g., every 2-3 months) thereafter as clinically indicated.1, 50
Congestive Heart Failure and Left Ventricular Dysfunction
Congestive heart failure and left ventricular dysfunction have been reported during imatinib therapy, mostly in geriatric patients or patients with a history of cardiac disease.1, 17, 50 In an international randomized phase 3 study in 1106 patients with newly diagnosed Ph+ chronic phase CML, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients receiving imatinib compared to 0.9% of patients receiving interferon alfa and cytarabine.1 In another randomized trial evaluating imatinib in patients with newly diagnosed chronic phase Ph+ CML, cardiac failure was observed in 1.1% of patients receiving imatinib and 2.2% of patients receiving nilotinib 300 mg twice daily; severe (grade 3 or 4) cardiac failure occurred in 0.7% of patients in each treatment group.1
Carefully monitor patients with cardiac disease, risk factors for cardiac disease, or a history of renal failure.1, 50 Evaluate and treat any patient with manifestations of cardiac or renal failure.1, 50
Hypereosinophilic Cardiac Toxicity
In patients with hypereosinophilic syndrome (HES) with occult infiltration of hypereosinophilic syndrome cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction, cardiogenic shock have been associated with HES cell degranulation upon initiation of imatinib therapy.1, 50 The condition has been reversed following administration of systemic corticosteroids, circulatory support measures, and temporary interruption of imatinib therapy.1, 50
Patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) and systemic mastocytosis may have high eosinophil levels.1, 50 Consider performing an echocardiogram and measuring serum troponin concentrations in patients with HES/chronic eosinophilic leukemia (CEL), and in patients with MDS/MPD or aggressive systemic mastocytosis associated with high eosinophil levels.1, 50 If the results of the echocardiogram or serum troponin concentrations are abnormal, consider the use of prophylactic therapy with systemic corticosteroids (1 to 2 mg/kg) for 1 to 2 weeks upon initiation of imatinib therapy.1, 50
Hepatotoxicity, sometimes severe, has been reported in patients receiving imatinib.1, 50 Fatal hepatic failure and severe hepatic injury requiring transplant have been reported with short- and long-term use.1 When imatinib is used in combination with chemotherapy, elevations in aminotransferase concentrations, hyperbilirubinemia, and acute hepatic failure have been reported.1
Monitor liver function tests (i.e., aminotransferase, bilirubin, alkaline phosphatase) prior to initiation of therapy and monthly thereafter or as clinically indicated.1, 50 If liver function test results are elevated, withhold imatinib and/or reduce dosage of the drug.1, 50
Grade 3 or 4 hemorrhage has occurred in 1.8% of patients receiving imatinib for first-line treatment of CML.1, 50 The incidence of hemorrhage is higher in patients receiving imatinib for the treatment of GIST (12.9%).1, 50 In patients with GIST, hemorrhagic events included GI bleeds, intratumoral bleeds, or both; GI tumor sites may have been the source of GI bleeds.1, 50 In a randomized trial in patients with newly diagnosed Ph+ chronic phase CML, GI hemorrhage occurred in 1.4% of patients receiving imatinib and in 2.9% of patients receiving nilotinib 300 mg twice daily.1 Postmarketing reports have also identified gastric antral vascular ectasia in patients receiving imatinib.1
Nausea, vomiting, and diarrhea occur frequently in patients receiving imatinib.1, 50 Administration with food and a large glass of water may minimize GI irritation.1, 50 Gastrointestinal perforation, sometimes fatal, has occurred rarely in patients receiving imatinib.1, 50
Bullous skin reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported in patients receiving imatinib.1, 50 Some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have recurred upon rechallenge of imatinib.1, 50 Following resolution or lessening of the bullous skin reaction, imatinib therapy has been reinitiated in some patients at a reduced dosage with or without concomitant administration of corticosteroids or antihistamines.1, 50
Hypothyroidism has been reported in imatinib-treated patients receiving levothyroxine replacement therapy after thyroidectomy; monitor serum TSH concentrations in such patients.1, 50
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.1, 50 No adequate and well-controlled studies to date in humans; however, spontaneous abortions and congenital anomalies have been reported in women exposed to imatinib during pregnancy in postmarketing reports.1 Avoid pregnancy during therapy.1, 50 Prior to initiation of imatinib therapy, verify pregnancy status of females of reproductive potential and advise such patients to use an effective contraceptive method during imatinib and for 14 days after discontinuation.1, 50 If used during pregnancy, apprise patients of potential fetal hazard.1, 50
Effects on Growth of Pediatric Patients
Imatinib may be associated with adverse reactions related to growth in children or pre-adolescents receiving the drug.1, 50 The long-term effects of imatinib treatment on growth in children is unknown.1, 50 Growth should be monitored during imatinib therapy in pediatric patients.1, 50
Tumor lysis syndrome, sometimes fatal, has been reported in patients with CML, GIST, ALL, and eosinophilic leukemia receiving imatinib.1, 50 Patients with high tumor burden or those with a high proliferative rate are at an increased risk of developing tumor lysis syndrome; monitor such patients and take appropriate precautions (e.g, adequate hydration, correct uric acid levels).1, 50
Impaired Driving/Machinery Operation
Motor vehicle accidents have been reported in patients receiving imatinib.1, 50 Dizziness, blurred vision, or somnolence may occur in patients receiving imatinib.1, 50 Advise patients to use caution when driving or operating machinery.1, 50
Reduced renal function has been observed in patients receiving imatinib therapy.1, 50 Monitor renal function prior to initiation of and during imatinib therapy, with close attention to patients with risk factors for renal dysfunction (e.g., preexisting renal impairment, diabetes mellitus, hypertension, congestive heart failure).1, 50
Doses of imatinib oral solution should be measured with an accurate milliliter (mL) measuring device.50 Use of a household teaspoon for measuring of doses is not recommended and may lead to overdosage.50 Patients should ask their pharmacist for an appropriate press-in bottle adapter and oral dispensing syringe and for instructions for measuring a correct dose.50
Can cause fetal harm based on human postmarketing reports and animal studies.1, 50
Imatinib and its metabolites are distributed into human milk; discontinue breast-feeding during therapy and for 1 month after the last dose.1, 50
Females and Males of Reproductive Potential
Imatinib can cause fetal harm; therefore, females of reproductive potential should verify pregnancy status prior to initiation of therapy.1, 50 Females of reproductive potential should also use an effective contraceptive method during therapy and for 14 days after the last dose of imatinib.1, 50
The risk of infertility in females or males of reproductive potential with imatinib has not been evaluated.1, 50
Safety and efficacy of imatinib in children younger than 1 years of age have not been established.1, 50
Safety and efficacy in pediatric patients with newly diagnosed Ph+ chronic phase CML and Ph+ ALL have been demonstrated.1, 50
Imatinib may be associated with adverse reactions related to growth in children or pre-adolescents receiving the drug.1, 50 The long-term effects of imatinib treatment on growth in children is unknown.1, 50 Growth should be monitored during imatinib therapy in pediatric patients.1, 50
In clinical trials in patients with CML, approximately 20% of patients were over 65 years of age.1 With the exception of a higher incidence of edema, no substantial differences in safety and efficacy relative to younger adults were observed.1
In the trial in patients with unresectable or metastatic GIST, 16% of patients were over 65 years of age.1 No substantial differences in safety and efficacy relative to younger adults were observed, but data are limited.1 In the adjuvant GIST study, 31% were over 65 years of age.1 With the exception of a higher incidence of edema, no substantial differences in safety and efficacy relative to younger adults were observed.1
Pharmacokinetics of imatinib are not significantly affected by mild or moderate hepatic impairment.1, 50
In patients with severe hepatic impairment, peak plasma concentrations and AUC of imatinib are increased by 63 and 45%, respectively, compared with patients with normal hepatic function; peak plasma concentrations and AUC of CGP74588 are increased by 56 and 55%, respectively, compared with patients with normal hepatic function.1 In patients with severe hepatic impairment, the manufacturer recommends reducing the imatinib dosage by 25%.1, 50
Mild and moderate renal impairment increases mean exposure to imatinib by 1.5- to 2-fold compared with patients with normal renal function.1 Data in patients with severe renal impairment are insufficient.1 The manufacturer recommends adjusting the dosage of imatinib in patients with moderate or severe renal impairment.1, 50
Adverse effects reported in at least 30% of patients were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain.1, 50
Metabolized in the liver, principally by CYP3A4 and to a lesser degree by CYP1A2, CYP2D6, CYP2C9, and CYP2C19.1 Imatinib is a strong competitive inhibitor of CYP isoenzymes 2C9, 2D6, and 3A4/5.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) inhibitors (e.g., atazanavir, clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, voriconazole): Potential pharmacokinetic interaction causing increased serum imatinib concentrations.1, 10
Grapefruit juice may increase imatinib plasma concentrations and should be avoided.1
CYP3A4 inducers (e.g., carbamazepine, dexamethasone, fosphenytoin, oxcarbamazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, St. John's wort): Potential pharmacokinetic interaction causing substantially decreased serum imatinib concentrations; alternative agents with less enzyme induction potential should be considered.1 For patients receiving a strong CYP3A4 inducer, such as rifampin or phenytoin, imatinib dosage should be increased by at least 50%, and clinical response should be monitored carefully.1, 50
Imatinib inhibits CYP3A4.1 Potential pharmacokinetic interaction (increased plasma CYP3A4-substrate concentrations) when imatinib is used with CYP3A4 substrates (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors, sirolimus, tacrolimus).1
Imatinib inhibits CYP2C9 and CYP3A4.1 Potential pharmacokinetic and pharmacologic interaction (enhanced anticoagulant effect).1 Patients requiring anticoagulation therapy should receive heparin or low molecular weight heparin.1
Imatinib appears to inhibit CYP2D6.1 Potential pharmacokinetic interaction (increased CYP2D6 substrate plasma concentrations); use caution with CYP2D6 substrates with a narrow therapeutic window (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus).1
Potential pharmacokinetic interaction (increased serum acetaminophen concentrations).1 No pharmacokinetic or safety data on concomitant use of acetaminophen and imatinib at doses exceeding 400 mg daily or with concomitant long-term use of imatinib and acetaminophen; caution is recommended.1, 8
Imatinib mesylate, an inhibitor of Bcr-Abl tyrosine kinase, is an antineoplastic agent.1, 50
The Philadelphia chromosome, characteristic of chronic myelogenous leukemia (CML), is created by a reciprocal translocation between chromosomes 9 and 22.2, 5, 8, 10, 11 Translocation between these chromosomes results in production of an abnormal protein (Bcr-Abl tyrosine kinase) that exhibits enhanced tyrosine kinase activity (i.e., increased phosphorylation of tyrosine residues);2, 11 phosphorylation of tyrosine residues on growth factor receptors is thought to be important in stimulating cell proliferation and inhibiting cell death (apoptosis). Imatinib competitively inhibits Bcr-Abl tyrosine kinase, thereby inhibiting tyrosine phosphorylation of proteins involved in Bcr-Abl signal transduction.5 The drug has been shown to inhibit proliferation and induce apoptosis of Bcr-Abl-positive cells as well as fresh leukemic cells from Ph+ CML.1
Imatinib also inhibits receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and PDGF-mediated and SCF-mediated cellular events.1, 8 Data from in vitro studies shows that imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells, which express an activating c-kit mutation.1
Imatinib is well absorbed after oral administration with a maximum serum concentration achieved within 2 to 4 hours after a dose.1 Imatinib is approximately 95% bound to plasma protein and has an elimination half-life of approximately 18 hours.1 Administration of 260 mg/m2 or 340 mg/m2 in pediatric patients achieved an AUC similar to that attained with a 400 mg dose in adults.1 Mean imatinib AUC increased proportionally with dose in adults but not in pediatric patients.1
Imatinib is metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, principally by the isoenzyme 3A4 (CYP3A4) and, to a lesser extent, by CYP1A2, CYP2D6, CYP2C9, and CYP2C19.1, 10 The active metabolite, an N -demethylated piperazine derivative, formed principally by CYP3A4, accounts for approximately 15% of total plasma concentrations of the drug.1 Approximately 68 and 13% of an oral dose of imatinib is excreted in feces and urine, respectively, as active and inactive metabolites within 7 days.1, 8 Apparent oral clearance appears to be similar in adults and pediatric patients.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Solution | 80 mg/mL | Imkeldi® | |
Tablets, film-coated | 100 mg (of imatinib)* | |||
Imatinib Tablets | ||||
400 mg (of imatinib)* | Gleevec® | Novartis | ||
Imatinib Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Novartis Pharma AG. Gleevec® (imatinib mesylate) tablets prescribing information. East Hanover, NJ; 2024 Mar. [Web]
2. Druker BJ, Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Investig . 2000; 105:3-7. [PubMed 10619854]
4. Food and Drug Administration. List of orphan designations and approvals. From FDA web site. [Web]
5. Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the Bcr-Abl tyrosine kinase in chronic myeloid leukemia. N Engl J Med . 2001; 344:1031-7. [PubMed 11287972]
6. Druker BJ, Sawyers CL, Kantarjian H et al. Activity of a specific inhibitor of the Bcr-Abl tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med . 2001; 344:1038-42. [PubMed 11287973]
7. Joensuu H, Roberts PJ, Sarlomo-Rikala M. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med . 2001; 344:1052-6. [PubMed 11287975]
8. Novartis, East Hanover, NJ: Personal communication.
9. Blanke CD, von Mehren M, Joensuu H et al. Evaluation of the safety and efficacy of an oral molecularly-targeted therapy, STI-571, in patients (pts) with unresectable or metastatic gastrointestinal stromal tumors (GISTS) expressing C-KIT. From ASCO website. [Web]
10. Anon. Gleevec (STI-571) for chronic myeloid leukemia. Med Lett Drugs Ther . 2001; 43:49-50. [PubMed 11402258]
11. Weisberg E, Griffin J. Mechanisms of resistance imatinib (STI-571) in preclinical models and in leukemia patients. Drug Resistance Updates . 2001; 4:22-8. [PubMed 11512149]
12. Mohammed M, Shin S, Deng S et al. Bcr/Abl gene amplification: a possible mechanism of drug resistance in patients treated with an ABL-specific kinase inhibitor. Blood . 2000; 96:344a.
13. Talpaz M, Donato NJ, Wu JY et al. Characterization of the clinical response to STI-571: biochemical evaluation of responsive and resistant advanced stage chronic myelogenous leukemia patients. Blood . 2000;96:735a.
14. Gorre ME, Mohammed M, Ellwood K et al. Clinical resistance to STI-571 cancer therapy caused by Bcr-Abl gene mutation or amplication. Sciencexpress . 2001;10:1126. Abstract.
15. Food and Drug Administration. MedWatch—Safety-related drug labeling changes: Gleevec (imatinib) [May 2003]. From FDA web site. [Web]
16. O'Brien SG, Guilhot F, Larson RA et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med . 2003; 348:994-1004. [PubMed 12637609]
17. Hohneker J. Dear healthcare provider letter re: severe congestive heart failure and left ventricular dysfunction in Gleevec treated patients. East Hanover, NJ: Novartis Pharmaceuticals; 2006 Oct 19.
19. Demetri GD, von Mehren M, Blanke CD et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med . 2002; 347:472-80. [PubMed 12181401]
20. FDA approves imatinib mesylate (Gleevec) as a single agent for the treatment of multiple indications. Rockville, MD: Food and Drug Administration; 2006 Oct 23. [Web]
21. Berman E, Nicolaides M, Maki RG et al. Altered bone and mineral metabolism in patients receiving imatinib mesylate. N Engl J Med . 2006; 354:2006-13. [PubMed 16687713]
22. Druker BJ, Guilhot F, O'Brien SG et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med . 2006; 355:2408-17. [PubMed 17151364]
23. Hochhaus A, O'Brien SG, Guilhot F et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia . 2009; 23:1054-61. [PubMed 19282833]
24. Cortes JE, Saglio G, Kantarjian HM et al. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol . 2016; 34:2333-40. [PubMed 27217448]
25. Hochhaus A, Saglio G, Hughes TP et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia . 2016; 30:1044-54. [PubMed 26837842]
26. Cortes JE, Gambacorti-Passerini C, Deininger MW et al. Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol . 2018; 36:231-237. [PubMed 29091516]
27. Champagne MA, Fu CH, Chang M et al. Higher dose imatinib for children with de novo chronic phase chronic myelogenous leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer . 2011; 57:56-62. [PubMed 21465636]
28. Kantarjian H, Sawyers C, Hochhaus A et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med . 2002; 346:645-52. [PubMed 11870241]
29. Hochhaus A, Druker B, Sawyers C et al. Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood . 2008; 111:1039-43. [PubMed 17932248]
30. Kantarjian HM, O'Brien S, Cortes JE et al. Treatment of philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res . 2002; 8:2167-76. [PubMed 12114417]
31. Sawyers CL, Hochhaus A, Feldman E et al. Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study. Blood . 2002; 99:3530-9. [PubMed 11986204]
32. Schultz KR, Carroll A, Heerema NA et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children's Oncology Group study AALL0031. Leukemia . 2014; 28:1467-71. [PubMed 24441288]
33. Shen S, Chen X, Cai J et al. Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA Oncol . 2020; 6:358-366. [PubMed 31944221]
34. Navarrete-Dechent C, Mori S, Barker CA et al. Imatinib Treatment for Locally Advanced or Metastatic Dermatofibrosarcoma Protuberans: A Systematic Review. JAMA Dermatol . 2019; 155:361-369. [PubMed 30601909]
35. Verweij J, Casali PG, Zalcberg J et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet . 2004; 364:1127-34. [PubMed 15451219]
36. Shah NP, Bhatia R, Altman JK, et al. Chronic myeloid leukemia, Version 2.2024. J Natl Compr Cancer Netw . 2024;22(1):43-69.
37. Hoelzer D, Bassan R, Dombret H et al. Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol . 2016; 27:v69-v82. [PubMed 27056999]
38. Blanke CD, Rankin C, Demetri GD et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol . 2008; 26:626-32. [PubMed 18235122]
39. Dematteo RP, Ballman KV, Antonescu CR et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet . 2009; 373:1097-104. [PubMed 19303137]
40. Joensuu H, Eriksson M, Sundby Hall K et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA . 2012; 307:1265-72. [PubMed 22453568]
41. Geoerger B, Morland B, Ndiaye A et al. Target-driven exploratory study of imatinib mesylate in children with solid malignancies by the Innovative Therapies for Children with Cancer (ITCC) European Consortium. Eur J Cancer . 2009; 45:2342-51. [PubMed 19362466]
42. Casali PG, Messina A, Stacchiotti S et al. Imatinib mesylate in chordoma. Cancer . 2004; 101:2086-97. [PubMed 15372471]
43. Stacchiotti S, Longhi A, Ferraresi V et al. Phase II study of imatinib in advanced chordoma. J Clin Oncol . 2012; 30:914-20. [PubMed 22331945]
44. Cassier PA, Gelderblom H, Stacchiotti S et al. Efficacy of imatinib mesylate for the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/pigmented villonodular synovitis. Cancer . 2012; 118:1649-55. [PubMed 21823110]
45. Chugh R, Wathen JK, Patel SR et al. Efficacy of imatinib in aggressive fibromatosis: Results of a phase II multicenter Sarcoma Alliance for Research through Collaboration (SARC) trial. Clin Cancer Res . 2010; 16:4884-91. [PubMed 20724445]
46. Penel N, Le Cesne A, Bui BN et al. Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): an FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up. Ann Oncol . 2011; 22:452-7. [PubMed 20622000]
47. Koon HB, Krown SE, Lee JY et al. Phase II trial of imatinib in AIDS-associated Kaposi's sarcoma: AIDS Malignancy Consortium Protocol 042. J Clin Oncol . 2014; 32:402-8. [PubMed 24378417]
48. Hodi FS, Corless CL, Giobbie-Hurder A et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol . 2013; 31:3182-90. [PubMed 23775962]
49. Guo J, Si L, Kong Y et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol . 2011; 29:2904-9. [PubMed 21690468]
50. Shorla Oncology. Imkeldi® (imatinib) oral solution prescribing information. Cambridge, MA; 2024 Nov.