Imatinib Mesylate Tablets Instructions

Approval date: November 06, 2007 Revision date: May 15, 2008 January 24, 2009 May 15, 2009 April 16, 2010 May 07, 2010 December 10, 2010
October 23, 2012
January 09, 2013
January 15, 2014
July 25, 2014
September 18, 2014
February 13, 2015
July 05, 2016
July 18, 2016
December 21, 2016
Year
Month
Date.
 Imatinib Mesylate Tablets Instructions
Please read the instructions carefully and use under the guidance of your physician.
 Drug Name
Generic name: Imatinib Mesylate Tablets
Trade name: Glivec® (Glivec®)
English name: Imatinib Mesylate Tablets
Hanyu Pinyin：Jiahuangsuan Yimatini Pian

 Ingredients
The active ingredient of this product is Imatinib Mesylate.
Chemical name: 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]phenyl]-benzamide methanesulfonate
Chemical structure formula.
Molecular formula: C29H31N7O-CH4SO3
Molecular weight: 589.7
 Properties
This product is a dark yellow to brownish yellow biconvex film-coated tablet.

 Indications
For the treatment of chronic phase, accelerated phase or acute phase of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML).
For the treatment of adult patients with unresectable and/or metastatic malignant gastrointestinal mesenchymal tumors (GIST).
Combination chemotherapy for the treatment of pediatric patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
For the treatment of adult patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
Information on safety and efficacy for the following indications was obtained primarily from foreign study data, with limited data from the Chinese population.
For the treatment of adult patients with eosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) with FIP1L1-PDGFRα fusion kinase.
For the treatment of adult patients with myelodysplastic syndromes/myeloproliferative disorders (MDS/MPD) with platelet-derived growth factor receptor (PDGFR) gene rearrangements.
For the treatment of adult patients with aggressive systemic mastocytic hyperplasia (ASM) without D816V c-Kit gene mutation or unknown c-Kit gene mutation.
For the treatment of unresectable, recurrent or metastatic dermatofibrosarcoma (DFSP).
For the adjuvant treatment of adult patients at significant risk of recurrence following surgical resection of a Kit (CD117)-positive GIST. Patients with very low and low risk of recurrence should not receive this adjuvant therapy.

 Specification
0.1g
 Dosage]
Treatment should be administered by a physician experienced in the treatment of patients with malignancies.
Imatinib mesylate should be taken with a meal and a large glass of water to minimize the risk of gastrointestinal disturbances.
Adults are usually given 400 mg or 600 mg once daily, as well as a daily dose of 800 mg i.e. 400 mg dose twice daily (in the morning and in the evening). Children and adolescents take once daily or in two divided doses (in the morning and in the evening).
Patients (including children) who are unable to swallow the tablets may disperse the tablets in gas-free water or apple juice (approximately 50 ml for 100 mg tablets and 200 ml for 400 mg). The suspension should be stirred and the tablets should be taken as soon as they disintegrate completely.
Treatment with this product should be continued as long as the patient continues to benefit.
 Therapeutic dose for patients with Ph+ CML
 Adults
The recommended dose of Imatinib Mesylate is 400 mg/day for patients in the chronic phase and 600 mg/day for patients in the acute and accelerated phases.
For first-line treatment of CML patients with WBC>50,000/µl, treatment experience is limited to patients who have received previous hydroxyurea therapy. The initiation of this treatment may require the addition of imatinib mesylate therapy.
In the absence of serious adverse drug reactions and if hematology permits, a dose increase from 400 mg/day to 600 mg/day or from 600 mg/day to 800 mg/day may be considered if disease progression has occurred at any time, satisfactory hematologic response has not been achieved after at least 3 months of treatment, no cytogenetic response has been achieved after 12 months of treatment, and the achieved hematologic and/or cytogenetic response reappears.
 Children and adolescents over 3 years of age
The efficacy and safety of this product in pediatric patients should be closely monitored and the dose should be adjusted if necessary.
Information on the safety and efficacy of this product in children and adolescents over the age of 3 years is mainly based on data from foreign clinical studies.
The recommended daily dose for pediatric patients is based on adult doses: 340 mg/m2 in the chronic phase and 340 mg/m2 in the acute phase (total dose not to exceed 600 mg/day), and the calculated dose should generally be adjusted up or down to the full 100 mg, and the dose for children under 12 years of age should generally be adjusted up or down to the full 50 mg.
There is no experience with treatment in children under 3 years of age.
 Therapeutic Dose for Patients with Ph+ALL
The recommended dose for adult patients is 600 mg/day.
The recommended dose for pediatric patients is 340 mg/m2 per day (total dose not to exceed 600 mg/day).
 Dose for patients with GIST
For patients with unresectable and/or metastatic malignant GIST, the recommended dose of imatinib mesylate is 400 mg/day.
In the absence of a satisfactory response after treatment, the dose may be considered to be increased from 400 mg/day to 600 mg/day or 800 mg/day if there are no serious adverse drug reactions.
In patients with GIST, imatinib mesylate should be continued unless the disease progresses.
The recommended dose for adjuvant therapy in adult patients after complete GIST resection is 400 mg/day. The duration of imatinib dosing in clinical studies was 3 years. The recommended duration of treatment is at least 36 months. The optimal duration of adjuvant therapy with imatinib is not known.
 Dosing for HES/CEL patients
The recommended dose of this product for HES/CEL treatment is based primarily on doses reported in foreign studies.
For HES/CEL with demonstrated presence of FIP1L1-PDGFR-α fusion kinase, the recommended starting dose is 100 mg/day. Increasing the 100 mg/day dose to 400 mg/day may be considered if adequate remission is not confirmed by appropriate testing after treatment and no adverse events occur.
 Dosage for patients with ASM
The recommended dose of this product for ASM treatment is mainly based on the doses reported in foreign studies.
The recommended dose of imatinib mesylate for the treatment of adult patients with ASM without D816V c-Kit mutation is 400 mg/day. If the c-Kit mutation status of a patient with ASM is unknown or undetectable, imatinib mesylate 400 mg/day should be considered for treatment when satisfactory remission is not achieved with other therapies.
The recommended starting dose of imatinib mesylate in patients with ASM with eosinophilia, a clonal hematologic disorder associated with FIP1L1-PDGFR-α fusion kinase, is 100 mg/day. An increase in the 100 mg dose to 400 mg may be considered if adequate remission is not confirmed by appropriate testing after treatment and no adverse events occur.
 Dosing for patients with MDS/MPD
The recommended dose of this product for MDS/MPD treatment is based on doses reported in foreign studies.
The recommended dose of imatinib mesylate in adults with hypereosinophilic syndrome and atypical MDS/MPD with PDGFR-α or -β gene rearrangement is 400 mg/day.
 Therapeutic Dose for Patients with DFSP
The recommended dose of Imatinib Mesylate for the treatment of DFSP is based on doses reported in foreign studies.
The recommended dose of imatinib mesylate for adult DFSP patients is 400 mg/day. The dose can be increased to 800 mg/day if needed.
 Dose adjustment after adverse reactions
If a serious non-hematologic adverse reaction (e.g., severe fluid retention) occurs during treatment with imatinib mesylate, the drug should be discontinued until the adverse reaction resolves, and then the dose should be adjusted according to the severity of that adverse reaction.
 Dose adjustment in case of severe hepatotoxicity
If bilirubin is elevated > 3 times the upper limit of the normal range or transaminase is elevated > 5 times the upper limit of the normal range, it is appropriate to discontinue imatinib mesylate until the above indicators are reduced to less than 1.5 or 2.5 times the upper limit of the normal range, respectively.
Later, imatinib mesylate treatment can be continued after dose reduction. The daily dose should be reduced from 400 mg to 300 mg, or from 600 mg to 400 mg or from 800 mg to 600 mg in adults; from 260 mg/m2 to 200 mg/m2 or from 340 mg/m2 to 260 mg/m2 in children and adolescents.
 Dose adjustment in neutropenia or thrombocytopenia
Ph+ CML accelerated or acute phase, Ph+ ALL (starting dose 600 mg/day, or 340 mg/m2/day in children and adolescents): If severe neutropenia and thrombocytopenia (neutrophils <0.5 x 109/L and/or platelets <10 x 109/L) are present, determine if the thrombocytopenia is related to leukemia (bone marrow aspiration or biopsy). If the hemocytopenia is not caused by leukemia, a dose reduction to 400 mg/day or 260 mg/m2/day in children and adolescents is recommended. If hematocrit persists for 2 weeks, further reduce the dose to 300 mg/day or 200 mg/m2/day in children and adolescents. if hematocrit persists for 4 weeks, discontinue until neutrophils ≥ 1 × 109/L and platelets ≥ 20 × 109/L. reuse at a dose of 300 mg/day; or 200 mg/m2/day in children and adolescents.
Patients with chronic phase CML and GIST (starting dose 400 mg/day or 260 mg/m2/day in children and adolescents): dosing should be discontinued when neutrophils are <1.0×109/L and/or platelets are <50×109/L, and should be resumed only when neutrophils are ≥1.5×109/L and platelets are ≥75×109/L. Treatment may be resumed at a dose of 400 mg/day or 260 mg/m2/day in children and adolescents. If critical values (neutrophils <1.0×109/L and/or platelets <50×109/L) reappear, treatment interruption is followed by a dose reduction to 300 mg/day or 200 mg/m2/day in children and adolescents.
 HES/CEL (starting dose of 100 mg/day).
Dosing should be discontinued when neutrophil ANC < 1.0 x 109/L and/or platelets < 50 x 109/L and should be resumed only when neutrophil ANC ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L. Dosing can be restarted with the previous dose (i.e., the dose prior to the occurrence of the serious adverse event).
 ASM (starting dose 100 mg/day).
Dosing should be discontinued when the neutrophil ANC is <1.0 x 109/L and/or platelets are <50 x 109/L and should be resumed only when the neutrophil ANC is ≥1.5 x 109/L and platelets are ≥75 x 109/L. Dosing can be restarted with the previous dose (i.e., the dose prior to the occurrence of the serious adverse event).
 HES/CEL, ASM, MDS/MPD (starting dose of 400 mg/day).
Dosing should be discontinued when neutrophils <1.0 x 109/L and/or platelets <50 x 109/L and should be resumed only when neutrophils ≥1.5 x 109 /L and platelets ≥75 x 109/L at a re-treatment dose of 400 mg/day. If critical values (neutrophils <1.0×109/L and/or platelets <50×109/L) reappear, the retreatment dose should be reduced to 300 mg.
 DFSP (dose 800 mg/day)
The drug should be discontinued when neutrophils <1.0×109/L and/or platelets <50×109/L and should be resumed only when neutrophils ≥1.5×109/L and platelets ≥75×109/L at a retreatment dose of 600 mg/day. If critical values (neutrophils <1.0×109/L and/or platelets <50×109/L) reappear, the retreatment dose should be reduced to 400 mg.
 Dose for patients with hepatic impairment
A minimum dose of 400 mg/day is recommended for those with mild to moderate hepatic impairment. There are no data available on the use of a dose of 400 mg/day in patients with severe hepatic impairment (bilirubin > 3 times the normal range). These patients should be treated with this product after careful weighing of risk assessment.
 Dosing in Patients with Renal Failure
The renal clearance of imatinib is negligible. For this reason, no reduction in systemic clearance is expected in patients with renal impairment. However, special care is still required in patients with severe renal impairment.
 Dosing in elderly patients
There is no special dose adjustment for elderly patients.

 [Adverse reactions].
Safety Summary
The overall safety profile of imatinib in human clinical use has been summarized and described through more than 12 years of experience with imatinib. In clinical development, most patients experience adverse events at some point in treatment. The most frequently reported adverse events (>10%) were neutropenia, thrombocytopenia, anemia, headache, dyspepsia, edema, weight gain, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue, and abdominal pain. The severity of these events was mild to moderate, and only 2% to 5% of patients experienced drug-related adverse events resulting in permanent treatment termination.
The safety differences between patients with Ph + leukemia and solid tumors were the higher incidence and severity of myelosuppression in patients with Ph + leukemia and GI and intra-tumor hemorrhage in patients with GIST and were likely due to disease-related factors. Myelosuppression, GI adverse events, edema and rash are common in both patient groups. Other GI conditions, such as obstruction, perforation and ulceration of the gastrointestinal tract, appear to be mostly indication-specific adverse reactions. Other prominent adverse events observed after exposure to imatinib and possibly causally related to the use of this product include hepatotoxicity, acute renal failure, hypophosphatemia, severe respiratory adverse reactions, tumor lysis syndrome, and developmental delay in children.
Depending on the severity of these adverse events, dose adjustment may be required. In rare cases, the drug will have to be discontinued based on adverse drug reactions.
Adverse reactions are listed in descending order of occurrence using the following provisions: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000), including case reports. The following adverse reactions are the incidence in clinical studies of CML and GIST
 Systemic abnormalities
Very common: fluid retention, edema (56%), fatigue (15%)
Common
Common: malaise, fever, chills, generalized edema, chills
Uncommon: chest pain, malaise
Infections and infections
Uncommon: sepsis, pneumonia1, herpes simplex, herpes zoster, upper respiratory tract infection, gastroenteritis, nasopharyngitis, sinusitis, cellulitis, influenza, urinary tract infection
Rare
See: fungal infections
Blood and lymphatic system abnormalities
Very common: neutropenia (14%), thrombocytopenia (14%) and anemia (11%)
Common
Seen: holocytopenia, febrile neutropenia
Uncommon: thrombocytosis, lymphopenia, myelosuppression, eosinophilia, lymphadenopathy
Rare
seen: hemolytic anemia
Metabolic and nutritional imbalances
Common
seen: loss of appetite
Uncommon: dehydration, hyperuricemia, hypokalemia, increased appetite, decreased appetite, gout, hypophosphatemia, hypercalcemia, hyperglycemia, hyponatremia
Rare
Rare: hyperkalemia, hypomagnesemia
Mental abnormalities
Common
Common: insomnia
Uncommon: depression, anxiety, decreased libido
Rare
Common: Blurred consciousness
Neurological abnormalities
Very common: headache 2 (11%)
Very common
See: dizziness, taste disturbance, sensory abnormalities, hyperalgesia
Uncommon: cerebral hemorrhage, syncope, peripheral neuropathy, drowsiness, migraine, memory impairment, sciatica, restless leg syndrome, tremor
Rare
Rare: increased intracranial pressure, convulsions, optic neuritis
Ocular abnormalities
Common
seen: eyelid edema, conjunctivitis, increased tearing, blurred vision, conjunctival hemorrhage, dry eyes
Uncommon: eye irritation, eye pain, orbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema
Rare
uncommon: optic nerve papillary edema, glaucoma, cataract
Ear and vagus abnormalities
Uncommon: vertigo, tinnitus, hearing loss
Cardiac abnormalities
Uncommon: palpitations, congestive heart failure3, pulmonary edema, tachycardia
Rare
Unusual: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion
Vascular abnormalities
Common
seen: flushing4, hemorrhage4
Uncommon: hematoma, hypertension, subdural hematoma, hypotension, chills in extremities, Raynaud’s phenomenon
Respiratory, thoracic and mediastinal abnormalities
Common
seen: epistaxis, dyspnea, cough
Uncommon: pleural effusion5, sore throat, pharyngitis
Rare
Common: pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage
Digestive system abnormalities
Very common: nausea (51%), vomiting (25%), diarrhea (25%), dyspepsia (13%), abdominal pain6 (14%)
Common
See: bloating, flatulence, constipation, gastroesophageal reflux, dry mouth, gastritis
Uncommon: stomatitis, mouth ulcers, gastrointestinal bleeding7, black stools, ascites, gastric ulcers, belching, esophagitis, vomiting blood, labyrinthitis, dysphagia, pancreatitis
Rare
See: colitis, intestinal obstruction, inflammatory bowel disease
Abnormalities of the hepatobiliary system
Common
seen: elevated liver enzymes
Uncommon: jaundice, hepatitis, hyperbilirubinemia
Rare
seen: liver failure9, hepatic necrosis9
Skin and subcutaneous tissue abnormalities
Very common: periorbital edema (32%), dermatitis/eczema/rash (26%)
Common
Seen: facial puffiness, pruritus, erythema, dry skin, alopecia, night sweats, photoallergic reactions
Uncommon: pustular rash, petechiae, contusions, hyperhidrosis, urticaria, broken nails, purpura, hyperpigmentation, hypopigmentation, psoriasis, exfoliative dermatitis, maculopapular rash, easy bruising, folliculitis, petechiae, thinning hair
Rare
See: acute febrile neutrophilic dermatosis (Sweet syndrome), angioneurotic edema, blistering rash, nail discoloration, erythema multiforme, leukocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalized eruptive pustulosis (AGEP)
Skeletal muscle, connective tissue and bone abnormalities
Very common: myospasm, painful myospasm (36%), skeletal muscle sarcoidosis including myalgia (14%), arthralgia, bone pain 8
Common
common: joint swelling
Uncommon: stiffness of joint muscles
Rare
See: muscle weakness, arthritis
Renal and urinary system abnormalities
Uncommon: acute renal failure, pain in the kidney area, frequent urination, hematuria
Reproductive system and breast abnormalities
Uncommon: gynecomastia feminization, erectile dysfunction, breast enlargement, scrotal edema, excessive menstruation, menstrual disorders, nipple pain, sexual dysfunction
Examination abnormalities
Very common: weight gain
Common
Common: Weight loss
Uncommon: increased blood alkaline phosphatase, increased blood creatine phosphokinase, increased blood creatinine, and increased lactate dehydrogenase
Rare
Rare: elevated blood amylase

 1 Adverse effects of pneumonia are most common in patients with progressive CML and GIST.
2 In patients with GIST, headache was the most common adverse effect.
3 Cardiac events, including congestive heart failure, occurring more commonly in patients with progressive CML than in patients with the chronic phase of CML were reported on a patient-year basis.
4 Flushing was the most frequent adverse reaction in patients with GIST, whereas bleeding (hematoma, hemorrhage) was the most frequent adverse reaction in patients with GIST and patients who developed progressive CML (CML-AP and CML-BC).
5 Pleural effusions were more common in patients with GIST and patients who developed progressive CML (CML-AP and CML-BC) than in the chronic phase of CML group.
6/7 Adverse reactions of abdominal pain and gastrointestinal bleeding were most common in patients with GIST.
8 Musculoskeletal pain and related adverse events are more common in patients with CML than in patients with GIST.
9 Cases of death due to liver failure and hepatic necrosis have been reported.
 Adjuvant therapy for GIST
The most commonly reported adverse reactions are similar to those reported in other clinical study populations and include diarrhea, fatigue, nausea, edema, hemoglobinopenia, rash, vomiting, and abdominal pain. No newly identified adverse reactions were reported in GIST adjuvant therapy. Fifty-seven (17%) and 11 (3%) of patients treated with imatinib and placebo, respectively, discontinued because of adverse reactions. The most commonly reported adverse reactions at discontinuation were edema, gastrointestinal dysfunction (nausea, vomiting, bloating, and diarrhea), fatigue, low hemoglobin, and rash.
The following are reports of adverse reactions that have occurred in post-marketing clinical applications. Because these adverse reaction reports are from studies with uncertain sample sizes, the frequency of these adverse reactions or the causal relationship between them and imatinib exposure is uncertain.
Infection and Transmission
Unknown: Hepatitis B virus reactivation
Neurological abnormalities
Unusual: cerebral edema
Ocular abnormalities
Rare
Unusual: vitreous hemorrhage
Cardiac abnormalities
Rare
seen: pericarditis, pericardial tamponade
Vascular abnormalities
Unusual: thrombosis/embolism
Very rare: anaphylaxis
Respiratory, thoracic and mediastinal abnormalities
Uncommon: acute respiratory failure1, interstitial lung disease
Digestive system abnormalities
Uncommon: intestinal obstruction, tumor bleeding/tumor necrosis, gastrointestinal perforation2
Rare
Unusual: diverticulitis, gastric sinus vasodilatation (GAVE)
Skin and subcutaneous tissue abnormalities
Unusual: hand-foot syndrome
Rare
seen: lichenoid keratosis, lichen planus
Very rare: toxic epidermolysis bullosa
Unknown: drug rash with eosinophilia and systemic symptoms (DRESS)
Skeletal muscle, connective tissue and bone abnormalities
Very common: musculoskeletal pain after drug withdrawal (including muscle pain, terminal pain, arthralgia, bone pain, spinal pain)
Rare
Rare: ischemic necrosis/hip necrosis, rhabdomyolysis/myopathy
Unknown: developmental delay in children
Reproductive system abnormalities
Very rare: luteal bleeding/ovarian cyst bleeding
Benign, malignant and unspecified tumors (including cysts and polyps)
Rare: tumor lysis syndrome
 1 Cases of advanced disease, severe infections and other serious comorbidities causing death have been reported
2 Deaths due to gastrointestinal perforation have been reported

 Description of some adverse drug reactions
Bone marrow suppression
Bone marrow suppression is extremely common in cancer patients treated with imatinib. Myelosuppression, thrombocytopenia, neutropenia, and anemia are the most commonly reported grade 3 and 4 laboratory test abnormalities. Overall, myelosuppression occurring with imatinib therapy in patients with CML is usually reversible and does not result in dose interruption or dose reduction in most patients. A small number of patients require discontinuation of the drug. Other events of complete cytopenia, lymphopenia, and myelosuppression have been reported.
Hematologic toxicity appears to be greatest at the highest dose and also appears to depend on CML disease stage, with grade 3 or 4 neutropenia and thrombocytopenia accompanying the acute and accelerated phases (
44% and 63%, respectively) were 4-fold and 6-fold higher than in patients with newly diagnosed CML CP (16.7% versus 8.9%, respectively).
These events can usually be countered by reducing the imatinib dose or interrupting imatinib therapy, but rarely require discontinuation of the drug. In patients with solid tumors (
i.e., GIST ) patients, the incidence of hematologic toxicity is less than in patients with Ph+ leukemia, with concomitant grade 3/4 neutropenia and thrombocytopenia of approximately 10% and 1%, respectively.
Hemorrhage
CNS and gastrointestinal bleeding is not uncommon in patients with CML with impaired bone marrow function at baseline. In the acute onset group of leukemia patients, bleeding is one of the recognized complications and may be caused by thrombocytopenia, or less commonly, abnormal platelet function. However, not all CNS and gastrointestinal bleeding that occurs in patients treated with imatinib is due to thrombocytopenia.
Clinically significant bleeding most commonly presents as gastrointestinal bleeding and occurs most frequently in patients with advanced CML and in patients with metastatic GIST, where the bleeding may be part of the underlying disease, tumor bleeding from tumor bleeding/tumor necrosis. The frequency of gastrointestinal bleeding observed in first-line CML and GIST adjuvant therapy is usually the lowest. Similarly, gastrointestinal vasodilatation (GAVE) is rarely reported during post-marketing Gleevec use.
 Edema and fluid retention
Edema is a common toxicity that occurs in more than 50% of all patients treated with imatinib for all indications. Edema is dose-related and its occurrence appears to be related to plasma levels. The most common presentation is periorbital edema, with lower extremity edema being somewhat less common. No specific treatment is usually required. Other fluid retention events occur more rarely, but there may be potential severity of some fluid retention due to the location of anatomic sites. The most common fluid retention event is pleural effusion, most commonly seen in patients with advanced CML and metastatic GIST. Heart failure usually occurs less frequently in patients with edema and fluid retention. Patients with advanced CML have a higher incidence of heart failure than other patients, which may be due to the poorer medical status of patients with advanced CML. The same trend of renal failure was observed in patients with edema and fluid retention.
In a clinical study, the incidence of events suggestive of congestive heart failure (CHF) in patients with newly diagnosed CML with imatinib versus IFN -α was 1.5% versus 1.1%, respectively. In patients with progressive CML (accelerated or acute phase), the frequency of congestive heart failure events was significantly higher in those with higher age or baseline hemoglobin below 8 g/dL. Among the treatments used for each indication, a higher frequency of CHF events was observed in patients with CML than in patients with GIST, which may indicate a difference in CHF-related risk factors for these diseases. In addition, an updated specific safety analysis published for cardiac events in the EORTC study of 942 patients with unresectable or metastatic GIST concluded that imatinib does not induce left ventricular failure in patients with GIST, with an observed incidence of approximately 0.2%, compared to up to 2% in the group with pre-existing cardiac disease.
Rash and serious skin adverse reactions
Generalized erythema, maculopapular rash, and pruritic rash have been reported to subside despite continued treatment. Some patients may experience pruritus without a rash and sometimes with epidermal peeling. Re-exposure to the product may result in reappearance of the rash in some patients, but not in all. These rashes are usually in response to antihistamines and topical steroids. Occasionally, systemic steroids are required.
Rashes have been observed in up to 1/3 of patients treated with imatinib for each indication. These rashes are often associated with pruritus and most often appear as erythematous, maculopapular or epidermolysis bullosa lesions on the forearm, trunk, face, or body. Skin biopsies show a toxic drug reaction combined with mixed cellular infiltration. Although most rashes are mild and self-limiting, more severe rare conditions such as Stevens-Johnson toxic epidermolysis bullosa, erythema multiforme, or DRESS may require treatment interruption or discontinuation. Not surprisingly, the incidence of skin reactions was higher in the GIST adjuvant trial than in the placebo group.
Hepatotoxicity
Hepatotoxicity may occur, is occasionally severe, and has been observed both preclinically and clinically.
Abnormal liver function tests, usually mildly elevated transaminases, but in a few patients elevated bilirubin levels. They usually occur within the first two months of treatment, but have also occurred as late as 6 to 12 months after the start of treatment. These indicator levels usually return to normal after 1-4 weeks of stopping treatment.
Hypophosphatemia
Low serum phosphate and hypophosphatemia (up to grade 3/4) have been observed more commonly across treatment indications, but the source and clinical significance of this finding have not been determined. Imatinib has been shown to inhibit the differentiation of human monocytes into osteoblasts. This decline is accompanied by a concomitant decrease in the resorption capacity of these cells as well. A dose-dependent decrease in RANK-L was observed in osteoclasts in the presence of imatinib. Sustained inhibition of osteoclast activity may lead to a counter-regulatory response, resulting in increased PTH levels. The clinical relevance of the results of preclinical studies is unclear, and the relationship with adverse skeletal events such as fractures has not been confirmed.
Serum phosphate was not routinely tested in all studies in the clinical development program. Although it was initially hypothesized that hypophosphatemia might be dose-dependent, interpretable results from the 24-month Phase III TOPS study (designed to explore the dose-dependence of safety endpoints in patients with newly diagnosed CML) showed that the Grade 3/4 decreases in serum phosphate or serum calcium levels that occurred in patients receiving 400 mg and 800 mg were 19.1% vs. 15.5% and 5.1% vs. 0.9%.
Gastrointestinal obstruction, perforation or ulceration
Gastrointestinal ulceration has been observed in a small proportion of patients treated with imatinib for each indication and may manifest as local irritation in a very large proportion of cases. Tumor bleeding/tumor necrosis, obstruction, and gastrointestinal perforation appear to be disease-related and occur only or more commonly in patients with GIST. In cases of metastatic GIST, tumor necrosis may occur in response to the tumor and rarely results in perforation. Gastrointestinal obstruction/bowel obstruction is most common in the GIST population (the condition may be due to tumor obstruction in metastatic GIST) and in the adjuvant treatment of prior GI surgical adhesions.
Tumor lysis syndrome
A causal relationship between tumor lysis syndrome and imatinib therapy is considered likely, but some cases may be associated with combined medications and other independent risk factors.
Developmental Delay in Children
Imatinib may affect stature in children, especially in prepubertal children. Although there is limited information on cases of growth retardation in the treatment of CML, a causal relationship between growth retardation and imatinib treatment in children cannot be ruled out.
Serious respiratory adverse drug reactions
Serious respiratory events, sometimes fatal, have been observed with treatment with imatinib, including acute respiratory failure, pulmonary hypertension, interstitial lung disease, and pulmonary fibrosis. In many cases, pre-existing cardiac or pulmonary disease may be associated with numerous serious respiratory events.
Abnormal laboratory tests
Hematologic system
Hematocrit, particularly neutropenia and thrombocytopenia, was reported in all studies in patients with CML, with a higher incidence at the high dose of >750 mg/day (phase I study), however the incidence of hematocrit was also significantly dependent on disease stage. The incidence of hemocytopenia was less in patients with newly diagnosed CML than in other CML patients. 3 or 4 degrees of neutropenia (ANC<1.0×109/L) and thrombocytopenia (platelet count<50×109/L) were less frequent in the acute and accelerated phases (59% to 64% for neutropenia and 44% to The incidence of neutropenia and thrombocytopenia in the acute and accelerated phases (59%-64% and 44%-63%, respectively) was 4 and 6 times higher than in patients with newly diagnosed chronic phase (16.7% for neutropenia and 8.9% for thrombocytopenia). The prevalence of grade 4 neutropenia (ANC<1.0×109/L) and thrombocytopenia (platelet count< 50×109/L) in patients with newly diagnosed chronic phase CML was 3.6% and <1%, respectively. The median duration of neutropenia and thrombocytopenia occurring was 2 to 3 weeks and 3 to 4 weeks, respectively. For such events, they can generally be relieved by dose reduction or suspension of the drug, with only isolated cases requiring long-term discontinuation of the drug for this purpose. The most common toxic reactions in pediatric CML patients are grade 3 or 4 hematocrit, including neutropenia, thrombocytopenia, and anemia. These toxic reactions usually occur in the first few months of first treatment.
In patients with GIST, the incidence of grade 3 and 4 anemia was 5.4% and 0.7%, respectively, and at least some of these patients were associated with gastrointestinal or intra-tumor bleeding. the incidence of grade 3 and 4 neutropenia was 7.5% and 2.7%, respectively, while the incidence of grade 3 thrombocytopenia was 0.7% and no patients experienced grade 4 thrombocytopenia. Decreases in complete blood cell and neutrophil counts occurred mainly during the first 6 weeks of treatment, and cell counts remained relatively stable thereafter.
 
 Biochemical examination
Severe transaminase elevations (<5%) or bilirubin elevations (<1%) have been observed in patients with CML, which resolved with dose reduction or discontinuation (median duration of approximately one week), and less than 1% of patients had long-term discontinuation due to abnormal liver function laboratory tests. 6.8% of patients with GIST (study B2222) had grade 3 or 4 serum alanine aminotransferase (ALT) elevations. In GIST patients (study B2222), 6.8% had elevated grade 3 or 4 serum alanine aminotransferase (ALT) and 4.8% had elevated grade 3 or 4 serum aspartate aminotransferase (AST). The incidence of elevated bilirubin is less than 3%.
Cases of cytolytic, cholestatic hepatitis or liver failure, some of which are fatal, may also be seen.
 [Contraindications].
Contraindicated in persons with hypersensitivity to the active substance or any of the excipient components of the drug.

 Precautions】
Significant reductions in left ventricular ejection fraction (LVEF) and symptoms of congestive heart failure have been reported in patients treated with this product. In animal studies, c-ABL enzyme inhibitors have been shown to cause a strong response in cardiomyocytes, and cardiac disease has been reported in carcinogenicity tests in rats. Therefore, patients at risk of cardiovascular disease or with cardiac disease should be closely monitored. Elderly patients treated with this product or those with a history of cardiac disease should first have their left ventricular ejection fraction (LVEF) measured, and patients with significant symptoms of heart failure during treatment should be thoroughly examined and treated accordingly according to clinical symptoms.
It is advisable to check the whole blood picture once a week in the first month of Imatinib mesylate treatment, once every two weeks in the second month, and as needed thereafter (e.g., once every 2-3 months). If severe neutropenia or thrombocytopenia occurs, the dose should be adjusted (see [DOSAGE AND ADMINISTRATION]).
Liver function (transaminases, bilirubin and alkaline phosphatase) should be checked before starting treatment and subsequently once a month or as clinically determined, and the dose should be adjusted if necessary. Blood and liver enzymes should be monitored in patients with mild, moderate or severe hepatic impairment. (See [Dosage], [Adverse Reactions] and [Pharmacokinetics]). Exposure to imatinib mesylate may be increased in patients with hepatic failure, and the product should be used with caution in patients with hepatic impairment. Imatinib mesylate should be used only after careful risk-benefit ratio assessment in patients with severe hepatic failure (see [DOSAGE AND ADMINISTRATION]). It should be borne in mind that patients with GIST may have liver metastases, which may increase the impairment of liver function. Transient hepatotoxicity has been observed in combination of imatinib with high-dose chemotherapy agents, with patients experiencing elevated transaminases and hyperbilirubinemia. Hepatic insufficiency may result when chemotherapy is combined with imatinib, and care should be taken to monitor liver function (see [Adverse Reactions]). Concomitant administration of imatinib mesylate and CYP3A4 inducers (see [Drug Interactions]) significantly reduces the total exposure to imatinib and therefore increases the risk of potential treatment failure. Therefore, the combination of imatinib mesylate with CYP3A4 inducers should be avoided. Caution should be exercised when combining imatinib mesylate with rifampin or other strong CYP3A4 inducers, ketoconazole or other strong CYP3A4 inhibitors, CYP3A4 substrates with a narrow therapeutic window (e.g., cyclosporine or pimozide), or CYP2C9 substrates with a narrow therapeutic window (e.g., warfarin and other coumarin derivatives) (see [Drug Interactions]).
Severe fluid retention (pleural fluid, edema, pulmonary edema, ascites, and superficial swelling) occurs in approximately 2.5% of newly diagnosed CML patients taking imatinib mesylate, and therefore regular weight monitoring is recommended. Weight gain should be carefully evaluated and appropriate supportive therapy should be administered if necessary. Fluid retention, especially in pediatric patients, may not present with recognizable edema.
Fluid retention can exacerbate or lead to heart failure, and there is no experience with the clinical use of imatinib mesylate in patients with severe heart failure (Class III-IV according to the New York Heart Association classification). Patients with a history of heart disease, heart failure risk factors, or renal failure need to be monitored closely; any patient with signs or symptoms of heart failure or renal failure should be evaluated and treated; patients with glaucoma should also be used with caution (see [ Adverse Reactions]).
The development of cardiogenic shock/left ventricular dysfunction in certain patients with eosinophilic syndrome (HES) with occult infiltration of HES cells in the myocardial tissue has been shown to be associated with the degranulation of HES cells that occurred at the time of initiation of imatinib. Improvement can be reported with systemic steroid hormones, circulatory support therapy, and temporary discontinuation of imatinib. Myelodysplastic/myeloproliferative disorders and systemic mastocytosis may be associated with high eosinophil concentrations. Echocardiography and measurement of serum troponin should therefore be considered in patients with HES/CEL, MDS/MPD or hypereosinophilic granulocyte-induced SM. If any of these measurements are abnormal, systemic steroid therapy (1-2 mg/kg) should be administered prophylactically for 1-2 weeks with concomitant treatment with imatinib.
Gastrointestinal bleeding
In the GIST clinical trial, gastrointestinal bleeding was reported in 8 patients (5.4%) and intra-tumor bleeding in 4 patients (2.7%). Depending on the site of the tumor, intra-tumor bleeding may occur in the abdominal cavity or in the liver. Intra-tumor bleeding in such patients may also present as gastrointestinal bleeding. In addition, gastric sinus vasodilation (GAVE) has been reported in post-marketing experience in patients with CML, ALL and other diseases as a rare cause of gastrointestinal bleeding. Therefore, patients should be monitored for gastrointestinal symptoms during the initiation and duration of Gleevec therapy. Discontinuation of Gleevec therapy may be considered when needed.
Tumor lysis syndrome
Cases of tumor lysis syndrome (TLS) have been reported in patients treated with imatinib. Given the potential for TLS, it is recommended that clinically significant dehydration be corrected and high uric acid levels be treated prior to treatment with imatinib
Hepatitis B virus reactivation
Hepatitis B virus
(HBV) reactivation of HBV may occur in chronic carriers after receiving a BCR-ABL tyrosine kinase inhibitor (TKI), such as imatinib. In some cases, HBV reactivation associated with the use of BCR-ABL TKI analogues has led to acute liver failure or fulminant hepatitis, and consequently to liver transplantation or a fatal outcome.
Patients need to be tested for the presence of hepatitis B virus infection before starting imatinib therapy. Patients currently on imatinib are required to undergo baseline hepatitis B virus testing to identify chronic hepatitis B virus carriers. Patients who are serologically positive for hepatitis B virus (including those with active disease) and those who are tested positive for hepatitis B virus during treatment should consult with a specialist in liver disease and hepatitis B treatment prior to initiating imatinib therapy. Patients with hepatitis B virus who require imatinib treatment should be closely monitored for signs and symptoms of active hepatitis B virus infection throughout the duration of treatment and for several months after termination of treatment.
Laboratory Tests
A complete blood count should be performed periodically during treatment with this product. Patients with CML treated with this drug often have neutropenia or thrombocytopenia. However, the development of neutropenia also depends on the stage of the disease and is more common in patients with accelerated CML or acute phase than in those with chronic CML. In this case, treatment should be interrupted or the dose reduced, see [DOSAGE AND ADMINISTRATION].
Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving this drug, see [DOSAGE AND ADMINISTRATION], and should be interrupted and/or reduced if abnormalities occur.
The product and its metabolites are barely excreted by the kidneys. Creatinine clearance (CrCL) decreases with age, but age has no significant effect on the pharmacokinetics of this product. Plasma exposure to imatinib appears to be higher in patients with renal insufficiency than in patients with normal renal function, possibly due to increased plasma levels of alpha acid glycoprotein (AGP) – an imatinib-binding protein – in these patients. Plasma exposure to imatinib did not correlate with renal insufficiency as evaluated by creatinine clearance, i.e., with mild (CrCL: 40-59 ml/min) and severe (CrCL: <20 ml/min) renal insufficiency. However, as suggested in [DOSAGE], the starting dose of imatinib may be reduced if not tolerated by the patient.
Preclinical studies have shown that imatinib does not readily cross the blood-brain barrier. It has not been studied in humans.
Results of a 2-year carcinogenesis study in rats have shown carcinogenesis in the penile foreskin, clitoris, kidney and bladder; no increase in bladder or kidney cancer has been reported in humans.
Hypothyroidism has been reported in thyroidectomized patients treated with levothyroxine during treatment with this product, and their TSH levels should be monitored in such patients.
Children and adolescents
Developmental delays have been reported in children and preadolescents receiving imatinib. The long-term effects of extended treatment with imatinib on development in children are not known at this time. Therefore, close monitoring of development in children on imatinib is recommended (see [Adverse Reactions]).
Effects on the ability of drivers and machine manipulators
Motor vehicle accidents have been reported in patients treated with imatinib, and most of these reports were not suspected to have been caused by imatinib. Adverse reactions to this product alert patients that they may experience dizziness, blurred vision, or drowsiness during treatment, and therefore caution should be taken when driving or manipulating machinery.

 Pregnant women and nursing mothers
Pregnancy
Animal studies have shown reproductive toxicity (see the reproductive toxicity section of the toxicology study).
There are no clinical trials of Imatinib in pregnant women. There have been post-marketing reports of spontaneous abortions and infant congenital anomalies in women taking Gleevec. Imatinib mesylate should be used during pregnancy only if the expected benefit outweighs the potential risk to the fetus. If imatinib mesylate is administered during pregnancy, the potential risk to the fetus must be communicated. Women of childbearing age should be advised to use highly effective contraception while taking imatinib mesylate. Highly effective contraception is a method of birth control that has a low failure rate when used consistently and correctly (i.e., less than 1% per year).
 Breastfeeding
Imatinib and its metabolites can be secreted into human breast milk. The concentration ratios of imatinib and its metabolites in breast milk plasma are 0.5 and 0.9, respectively, indicating a higher proportion of metabolites entering breast milk. Based on the combined concentrations of imatinib and its metabolites and the infant’s maximum daily intake of breast milk the overall infant drug exposure was low, accounting for only about 10% of the efficacious amount. However, because the effect of low doses of imatinib on infant exposure is not known, women who are taking this product should not breastfeed. There have been post-marketing reports of spontaneous abortions and congenital anomalies in infants in women taking imatinib.
Fertility
Human studies of male patients receiving imatinib and its effects on male fertility and spermatogenesis have not been conducted. Male patients treated with imatinib who are concerned about effects on fertility should consult their physician as detailed in [Pharmacology and Toxicology].
Pediatric Use]
For the use of this product in children over 3 years of age, please see [Dosage]. Data on the safety and efficacy of the drug in Chinese children are limited, mainly from overseas studies in children.
There is no experience with children under 3 years of age.
Geriatric use]
Age-related decrease in creatinine clearance has no significant effect on the pharmacokinetics of imatinib mesylate.
Elderly patients treated with this product or those with a history of cardiac disease should first have their left ventricular ejection fraction (LVEF) measured. Patients with significant symptoms of heart failure during treatment should be thoroughly examined and treated accordingly according to clinical symptoms.
 [Drug Interactions].
Drugs that may alter the plasma concentration of Imatinib
CYP3A4 inhibitors: The drug exposure to imatinib was significantly increased in healthy subjects after concomitant administration of a single dose of ketoconazole (CYP3A4 inhibitor) (mean maximum plasma concentration (Cmax) and area under the imatinib curve (AUC) could be increased by 26% and 40%, respectively). There is no experience with concomitant administration with other CYP3A4 inhibitors (e.g., itraconazole, erythromycin, and clarithromycin).
CYP3A4 inducers: Rifampin administration in healthy volunteers resulted in a 3.8-fold increase in clearance of imatinib (90% confidence interval = 3.5-4.3-fold) but a 54%, 68% and 74% decrease in Cmax, AUC (0-24) and AUC (0-8), respectively. In clinical studies, plasma concentrations of imatinib were found to decrease after concomitant administration of phenytoin drugs, resulting in reduced efficacy. Similar results have been observed in patients with malignant glioma receiving enzyme-inducing anti-epileptic drugs (EIAEDs) such as carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and dexpanthenol, concomitantly with this product. The AUC of imatinib decreased to 73% compared with no concomitant EIAEDs, and other CYP3A4-inducing agents, such as dexamethasone, catamizine, and phenobarbital, may have similar problems, so concomitant administration of imatinib with CYP3A4-inducing agents should be avoided. In two published studies, imatinib caused a 30% to 32% decrease in the AUC of this product when combined with preparations containing St. John’s wort.
Imatinib mesylate can cause changes in plasma concentrations of the following drugs
Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) by 2-fold and 3.5-fold, respectively. It should be kept in mind that imatinib can increase plasma concentrations of other drugs metabolized by CYP3A4 (e.g., benzodiazepines, dihydropyridines, calcium channel antagonists, and other HMG-CoA reductase inhibitors). Therefore, caution should be exercised when this drug and CYP3A4 substrates with a narrow therapeutic window (e.g., cyclosporine, pimozide) are administered concomitantly.
At concentrations similar to those inhibiting CYP3A4 activity, imatinib also inhibits CYP2D6 activity in vitro and therefore has the potential to increase systemic exposure to CYP2D6 substrates when administered concomitantly with imatinib mesylate, although it has not been specifically studied and caution is advised.
Imatinib also inhibits CYP2C9 and CYP2C19 activity in vitro, and prolonged prothrombin time has been seen with concomitant administration of warfarin. Therefore, short-term monitoring of prothrombin time should be performed at the beginning and end of imatinib mesylate treatment or at the time of dose change if dicoumarol is being administered concurrently.
Imatinib at a dose of 400 mg twice daily had a weak inhibitory effect on CYP2D6-induced metabolism of metoprolol, with an approximate 23% increase in Cmax and AUC of metoprolol. There does not appear to be a risk factor for drug-drug interactions when imatinib is combined with CYP2D6-inducing agents such as metoprolol, and dose adjustment may not be necessary.
In vitro experiments have shown that imatinib inhibits the O-glucuronidation of acetaminophen (Ki of 58.5 μM).
Concomitant administration of gleevec (400 mg/day for 8 days) and acetaminophen/paracetamol (single dose of 1000 mg on day 8) in patients with CML did not alter the pharmacokinetics of acetaminophen/paracetamol.
The pharmacokinetics of Gleevec were not altered with a single dose of acetaminophen/paracetamol.
There are no PK or safety data on concomitant use of Gleevec at doses greater than 400 mg/day or on long-term concomitant use of acetaminophen/paracetamol and Gleevec.
One patient who was routinely taking acetaminophen for fever died of acute hepatic failure; the exact cause of death is not known, but patients should be warned to avoid over-the-counter and prescription medications containing acetaminophen.
[Drug Overdose].
Experience with dosing above therapeutic doses is limited. There have been only spontaneous reports of isolated cases and case reports of overdose in the literature. Usually these cases have improved or recovered. If an overdose occurs, the patient should be closely monitored and given appropriate supportive therapy.
The following events have been reported at different doses.
Adult overdose.
1200 to 1600 mg (duration ranging from 1 to 10 days): nausea, vomiting, diarrhea, rash, erythema, edema, swelling, fatigue, muscle cramps, thrombocytopenia, various types of hemocytopenia, abdominal pain, headache, loss of appetite.
1800 to 3200mg (daily dose up to 3200mg for 6 days): weakness, myalgia, elevated CPK, elevated bilirubin, gastrointestinal pain.
6400mg (single dose): nausea, vomiting, abdominal pain, fever, facial swelling, decreased neutrophil count, and elevated transaminases in one patient reported in the literature.
8-10g (single dose): vomiting and gastrointestinal pain were reported.
Overdose in children
A three-year-old boy exposed to a single dose of 400 mg of drug developed vomiting, diarrhea, and anorexia, and another three-year-old boy exposed to a single dose of 980 mg of drug developed decreased white blood cell counts and diarrhea.
Clinical Trials]
All of the following are reports of foreign studies.
Chronic myeloid leukemia clinical studies
Three open, uncontrolled phase II clinical studies were conducted in patients with Ph+ chronic myeloid leukemia in the acute, accelerated, and chronic phases who failed treatment with alpha-interferon (INF).
In a large, open, controlled phase III clinical trial, patients were newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia patients (Ph+ CML). Treatment of children and adolescents was conducted in two phase I studies. Of the clinical study cases, 38-40% of patients were ≥60 years of age and 10-12% were ≥70 years of age.
Newly diagnosed chronic phase: A phase III clinical trial compared the efficacy of imatinib mesylate monotherapy with the combination of interferon alpha (IFN) and cytarabine (Ara-C). Patients who were treatment-naive (did not achieve a complete hematologic response (CHR) at 6 months, had an increased white blood cell count, did not achieve a major cytogenetic response (MCyR) at 24 months), had a loss of efficacy (complete cytogenetic response or loss of major cytogenetic response) or were severely intolerant of treatment could be crossed over from one treatment arm to the other. Patients in the imatinib mesylate treatment arm receive a daily dose of 400 mg of this product. Patients in the interferon treatment arm receive interferon 5 MIU/m2/day subcutaneously; in combination with Ara-C 20 mg/m2/day subcutaneously for 10 days per month.
The response results in the experimental study of newly diagnosed CML are shown in the table below (data at 60 months).
 Imatinib mesylate
IFN + Ara-C (best response rate) n=553 n=553 Hematologic response
 
 CHR n (%) 534 (96.6) 313 (56.6) [95 % confidence interval] [94.7, 97.9] [52.4, 60.8] Cytogenetic response
 
 Major cytogenetic response rate n (%) 490 (88.6) 129 (23.3) [95 % confidence interval] [85.7, 91.1] [19.9, 27.1] Complete cytogenetic response rate n (%) 454 (82.1) 64 (11.6) Partial cytogenetic response rate n (%) 36 (6.5) 65 (11.8) Molecular response
 
 Major molecular response at 12 months (%) 40*2*Major molecular response at 24 months (%) 54 NA***p<0.001, Fisher’s exact test
** Data incomplete, only 2 patients in the sample
At 60 months, progression-free survival was 83.2% with 95% confidence interval (79, 87) in the imatinib mesylate group; 64.1% (59, 69) in the control group (p < 0.001). The rate of disease progression in the imatinib mesylate group was 3.3% in the first year, 7.5% in the second year, and 4.8%, 1.5%, and 0.9% in the third, fourth, and fifth years, respectively.
The degree of cytogenetic response had a significant impact on the long-term prognosis of patients in the imatinib mesylate group. Ninety-seven percent and 93% of patients who achieved a complete and partial cytogenetic response at 12 months of treatment, respectively, had not progressed to the accelerated or acute phase at month 60; whereas only 81% of patients who did not achieve a major cytogenetic response at 12 months of treatment did not progress to advanced CML at month 60 (overall comparison p<0.001; complete p=0.20 between cytogenetic response and partial cytogenetic response). The rates of non-progression at 60 months for patients who reached complete cytogenetic response, partial cytogenetic response and did not reach major cytogenetic response were 99%, 90% and 83%, respectively, with complete and partial cytogenetic response showing a statistical difference in long-term prognosis at 18 months (p<0.001).
Molecular monitoring may provide additional prognostic information. Patients who achieved a complete cytogenetic response at 12 months of treatment and whose BCR-ABL transcript levels decreased by at least 3 log were significantly more likely to maintain progression-free survival at 60 months than those who only achieved a complete cytogenetic response and whose BCR-ABL transcript levels decreased by less than 3 log (95% vs 89%, p=0.068), and more so than those who did not achieve a complete cytogenetic response at 12 months. genetic response (70%, p<0.001). If only the possibility of progression to the accelerated/acute phase was considered, the progression-free survival rates were 100%, 95%, and 88% for the above three categories of patients, respectively (overall comparison, p<0.001; CCyR with MMR vs. CCyR without MMR, p=0.007). Using an 18-month cut-off, the odds of not progressing to the accelerated/acute phase at 60 months were 100% for those who achieved a complete cytogenetic response with a major molecular response, 98% for those who achieved a complete cytogenetic response without a molecular response, and only 87% for those who did not achieve a complete cytogenetic response (overall comparison p<0.001; CCyR with MMR versus CCyR without MMR (comparison, p=0.105).
Quality of life was evaluated using the validated FACT-BRM questionnaire, and all aspects were rated higher in the imatinib mesylate group than in the IFN-Ara-C group, and quality of life data indicated that patients treated with imatinib mesylate were able to maintain a happy mood.
Patients in the chronic phase who failed alpha-interferon therapy: 532 patients in the chronic phase who failed interferon therapy received imatinib at a starting dose of 400 mg once daily.
Sixty-five percent of patients achieved a major cytogenetic response, 53% achieved a complete cytogenetic response, and 95% achieved a complete hematologic response.
(Accelerated phase: 235 patients were enrolled in the accelerated phase, 63% of whom had received other treatment in the accelerated phase, 77 of 235 patients received imatinib 400 mg once daily and 158 received 600 mg once daily). As a result, 71.5% of patients achieved a definitive hematologic response, 42% achieved a complete hematologic response, 28% achieved a major cytogenetic response (i.e., reduction of Philadelphia chromosome-positive cells in division to <35%), and 20% achieved a complete cytogenetic response. Analysis with hematologic response as the primary endpoint revealed no significant differences between the 400 mg and 600 mg dose groups, but the improvement in cytogenetic response was more pronounced in the 600 mg dose group and its duration was longer. In this study, the time to disease progression was significantly different in the 600 mg dose group.
Acute phase: 260 patients in the acute phase were enrolled, 95 [37%] of whom had received chemotherapy before entering the accelerated or acute phase and 165 [63%] of whom had not received prior chemotherapy. 223 patients started treatment at a dose of 600 mg once daily. Using different complete hematologic responses as the primary efficacy, a positive hematologic response was obtained in 31% of patients (36% in patients who had not received treatment and 22% in patients who had received treatment) and a major cytogenetic response was observed in 15% of patients. Hematologic responses were higher in patients at 600 mg/day than in patients at 400 mg/day (33% and 16%, respectively; p=0.0220). The median survival times were 7.7 and 4.7 months for untreated and treated patients, respectively.
In an open, multicenter, phase II clinical trial of monotherapy, 51 pediatric patients with newly diagnosed untreated chronic-phase CML were enrolled and treated with imatinib at a dose of 340 mg/m2/day. Patients experienced rapid remission after imatinib treatment, with 78% achieving CHR after 8 weeks and 65% achieving complete cytogenetic response (CCyR) after 3 to 10 months, a rate comparable to that of adult patients.
Another phase I trial with a total of 31 pediatric patients in chronic phase of CML (15) or acute leukemia in acute phase of CML or Philadelphia chromosome-positive (16) were enrolled in a dose-escalating phase I trial who had received multiple prior treatments, 45% of whom had received bone marrow transplantation and 68% had received multi-drug chemotherapy. Patients received imatinib at the following doses, 260 mg/m2/day, 340 mg/m2/day, 440 mg/m2/day, and 570 mg/m2/day. Of the 13 patients with CML for whom cytogenetic data were obtained, 7 (54%) obtained a complete cytogenetic response and 4 (31%) obtained a partial cytogenetic response, corresponding to 85% obtaining a major cytogenetic response.
Clinical studies of gastrointestinal mesenchymal tumors (GIST)
An open, randomized, multinational Phase II clinical trial was conducted in patients with gastrointestinal mesenchymal tumors (GIST) that were not surgically resectable or metastatic. In this trial, 147 patients enrolled were randomized to receive oral imatinib 400 mg or 600 mg once daily for up to 36 months. The average treatment duration was 6 to 12 months (no longer than 36 months). These patients were between 18 and 83 years of age and had a pathological diagnosis of C-Kit-positive malignant gastrointestinal mesenchymal tumor (GIST) that was not surgically resectable and/or was metastatic.
The two dose groups of the population had
response rates were not significantly different, with many patients with stable disease at interim analysis achieving partial responses as treatment duration was extended (median follow-up time 31 months). The median time to disease response was 13 weeks (95% C.I.:12 to 23), the median time to treatment failure was 122 weeks (95% C.I.:106 to 147), and the overall study was 84 weeks (95% C.I.:71 to 109). Overall median survival data are not yet available; at 36 months of follow-up, Kaplan-Meier survival analysis estimated a 68% survival rate. There was no statistically significant difference in survival time for patients who achieved stable disease and partial response.
In two clinical trials (studies B2222 and S0033), patients were treated with a starting dose of 400 mg/day or 600 mg/day, with the dose increasing to 800 mg/day as disease progressed. In total, the dose was increased to 800 mg/day in 103 patients, and the increased dose resulted in partial responses in 6 patients and stable disease in 21 patients, for an overall clinical benefit rate of 26%. From the currently known safety data, the increase in dose to 800 mg/day does not appear to have affected the therapeutic safety of this product.
Clinical study of adjuvant therapy for gastrointestinal mesenchymal tumors (GIST)
Adjuvant therapy with Gleevec was studied in a multicenter, double-blind, placebo-controlled, randomized study (Z9001) with 713 patients. The patients’ age range was 18-91 years. After complete resection of primary GIST, patients were randomized to one of the following two groups: imatinib mesylate 400 mg/day or the corresponding placebo control group for 1 year. Patients enrolled included those with a histologically diagnosed immunochemically confirmed primary GIST expressing Kit protein, with a tumor ≥3 cm in longest diameter, and who underwent total resection 14 to 70 days prior to enrollment.
The effectiveness endpoint of the study was recurrence-free survival (RFS), which was the time between randomization and the date of recurrence or the date of death from any cause.
Imatinib significantly prolonged RFS, with 75% of patients in the imatinib group free of recurrence at month 38 compared with 20 months in the placebo group (95% CIs, [30-not estimable]; [14-not estimable]; (HR= 0.398 [0.259 to 0.610], p<0.0001)). The 12-month RFS was significantly better in the imatinib group than in the placebo group, with an RFS of 97.7% and 82.3%, respectively (p<0.0001). The relative risk of GIST recurrence during the first 12 months was 89% lower compared with the placebo group (HR= 0.113; 95% CI: 0.049 to 0.264).
A retrospective analysis of GIST patients with different risks of recurrence after primary resection according to tumor size, mitotic count, and primary tumor site was performed. mitotic data were available for 556 patients out of a population of 713 patients in the Z9001 trial. The subgroup analysis performed according to NIH and AFIP risk classification is presented below. Patients at low risk of recurrence did not receive clinical benefit from this adjuvant therapy.
Summary of RFS analysis of the Z9001 trial by NIH and AFIP risk classification criteria
Risk Criteria Risk Level Patient % Number of Events/Number of Patients Total HR (95% CI) RFS Rate (%) 12 months 24 months Gleevec vs. placebo Gleevec vs. placebo Gleevec vs. placebo NIH Low
29.5 0/86 vs. 2/90 N.E. 100 vs. 98.7 100 vs. 95.5 Medium
25.7 4/75 vs. 6/78 0.59 (0.17,2.10) 100 vs. 94.8 97.8 vs. 89.5 High
44.8 21/140 vs. 51/127 0.29 (0.18, 0.49) 94.8 vs. 64.0 80.7 vs. 46.6 AFIP Very low
20.7 0/52 vs. 2/63 N.E. 100 vs. 98.1 100 vs. 93.0 Low
25.0 2/70 vs. 0/69 N.E. 100 vs. 100 97.8 vs. 100 Medium
24.6 2/70 vs. 11/67 0.16 (0.03, 0.70) 97.9 vs. 90.8 97.9 vs. 73.3 High
29.7 16/84 vs. 39/81 0.27 (0.15, 0.48) 98.7 vs. 56.1 79.9 vs. 41.5 * Whole follow-up period
N.E. = not estimable
Another open phase III study (SSG XVIII/AIO) compared 12-month treatment with a 400 mg/day dose of Gleevec to 36-month treatment in patients after GIST resection and in the presence of any of the following: tumor diameter >5 cm, mitotic count at high magnification field of view (HPF) >5/50; or tumor diameter >10 cm, any mitotic count; or any tumor size, mitotic count >10/50 HPF or tumor rupture into the peritoneal cavity. A total of 397 patients signed informed consent and were randomized (199 in the 12-month treatment group and 198 in the 36-month treatment group) with a median age of 61 years (range 22-84 years). The median follow-up period was 54 months (from the date of randomization to the cut-off date of the data), and the total time from the first patient randomization to the cut-off date was 83 months.
The primary endpoint of the study was relapse-free survival (RFS), defined as the time from the date of randomization to the date of relapse or death from any cause.
RFS was significantly longer in the 36-month treatment group compared with the 12-month treatment group (overall hazard ratio (HR)=0.46 [0.32, 0.65], p<0.0001, HR over 12 months=0.42 [0.28, 0.61]). the total number of RFS events in the 12-month and 36-month treatment groups was 84 (42%) and 50 ( 25%).
In addition, overall survival (OS) was significantly longer in the 36-month treatment group compared to the 12-month treatment group (HR=0.45 [0.22, 0.89], p=0.0187). the total number of mortality events was 25 in the 12-month treatment group and 12 in the 36-month treatment group.
Gleevec treatment for 12 and 36 months
(SSGXVIII/AIO trial)
 12-month treatment group 36-month treatment group RFS %(CI) %(CI) 12 months 93.7 (89.2 to 96.4) 95.9 (91.9 to 97.9) 24 months 75.4 (68.6 to 81.0) 90.7 (85.6 to 94) 36 months 60.1 (52.5 to 66.9) 86.6 (80.8 to 90.8) 48 months 52.3 (44.0~59.8) 78.3 (70.8~84.1) 60 months 47.9 (39.0~56.3) 65.6 (56.1~73.4) Survival 36 months 94.0 (89.5~96.7) 96.3 (92.4~98.2) 48 months 87.9 (81.1~92.3) 95.6 (91.2 ~97.8) 60 months 81.7 (73.0 to 87.8) 92.0 (85.3 to 95.7) Kaplan-Meier estimates for primary endpoint of relapse-free survival (ITT cohort)
Kaplan-Meier estimates of overall survival (ITT group)
Clinical studies of Ph+ ALL
A total of 851 patients with newly diagnosed or relapsed/refractory Ph+ ALL were enrolled in 11 clinical trials, 10 of which were non-controlled trials and 1 was a randomized trial. Of these 851 patients, 93 pediatric patients (including 4 patients aged 18-22 years) were enrolled in an open, multicenter, nonrandomized phase III study.
Newly diagnosed Ph+ ALL
In a controlled trial of imatinib versus chemotherapy (ADE10), in which 55 newly diagnosed patients aged 55 years or older were enrolled, the complete hematologic response rate was significantly higher in the imatinib monotherapy group than in the chemotherapy group (96.3% vs 50%, p=0.0001). A complete hematologic response was achieved in 9 of 11 patients (81.8%) after rescue treatment with imatinib in patients who were ineffective or poorly treated with chemotherapy, a clinical outcome associated with a significantly lower BCR-ABL transcript in the imatinib-treated group compared to the chemotherapy group after 2 weeks of treatment (p=0.02). All patients continued to receive imatinib treatment or intensive chemotherapy after induction therapy, and BCR-ABL levels were consistent in both groups at 8 weeks. As expected at the time of study design, there were no significant differences in response period, disease-free survival or overall survival between the two groups, although patients who obtained a complete molecular response and the presence of minimal residual disease had a better prognosis according to the criteria of response duration (p=0.01) and disease-free survival (p=0.02).
A total of 211 patients with newly diagnosed Ph+ ALL were enrolled in four uncontrolled trials (AAU02, ADE04, AJP01 and AUS01) with results consistent with those described above. The combination of imatinib and chemotherapy resulted in a 93% complete hematologic response rate (147 of 158 evaluable patients achieved a complete hematologic response), a 90% major cytogenetic response rate (19 of 21 evaluable patients achieved a major cytogenetic response), and a 48% complete molecular genetic response rate (49 of 102 evaluable patients achieved a complete molecular genetic response).
Similarly, in 2 uncontrolled clinical trials (AFR09 and AIT04), 49 patients aged 55 years or older with newly diagnosed Ph+ ALL were enrolled and received imatinib + hormone or imatinib + hormone + chemotherapy, respectively. Complete hematologic responses were achieved in 89% of all patients and in 26% of 39 evaluable patients. disease-free survival (DFS) and overall survival (OS) exceeded 1 year in all 3 trials (AJP01, AUS01, AFR09), which was higher than historical controls (DFS p<0.001; OS p<0.01).
Efficacy of Imatinib in the Treatment of Adult Patients With Newly Diagnosed Ph+ ALL
Study name AAU02 ADE04 AJP01 AUS01 AFR09 AIT04 ADE10§ Imatinib
+ chemotherapy imatinib
and chemotherapy imatinib
+ chemotherapy imatinib
+ chemotherapy imatinib
+ chemotherapy/hormonal imatinib
+ hormonal imatinib
Chemotherapy Group 2 N (number of cases in which CHR could be assessed)12 45 80 21 29 18 27 26 CHR (%) 58 95 96 95 72 100 96 50* 95% confidence interval 28 – 85 85 – 99 89 – 99 76 – 100 53 – 87 82 – 100 81 – 100 30 – 70 CHR historical control (CHT) 51
(p<0.0001) 61 – 94
(p<0.01) 29
(p=0.003) N (total cases)24 47 80 20 30 19 28 27 1-year DFS (%) NA NA 61 ± 687 60 – 54 Median DFS (months) – – – – – 15 – 1-year OS (%) 61 ± 13NA 76 ± 5- 68 – 54 2-year OS (%) – NA – 75 – – – – Median OS (months) – – – – – – 20 – CHR = Complete hematologic response
CHT = chemotherapy
m = Months
NA = Not assessable
* p<0.01
§After induction therapy
** Initial 20 newly diagnosed and relapsed/refractory patients
&
Includes all patients with newly diagnosed, relapsed and acutely changed CML Pediatric patients: study I2301 is an open, multicenter, sequential design, non-randomized phase III study of a total of 93 pediatric, adolescent and adult Ph+ ALL patients (including 4 patients aged 18-22 years) enrolled who received imatinib (340 mg/m2/day) + intensive chemotherapy after induction therapy. In groups 1 to 5, patients received intermittent imatinib administration, with increasing duration of administration and progressively earlier initiation of gleevec therapy in each group in turn; group 1 received the lowest intensity of imatinib administration and group 5 had the highest intensity of administration (longest duration of administration [days] and continuous daily imatinib treatment given within the first chemotherapy course). In group 5 (n=50), continuous daily gleevec treatment plus chemotherapy was found to result in improved 4-year event-free survival (EFS), with lower data than historical control data (n=120) receiving standard chemotherapy without imatinib, 69.6% vs. 31.6%, respectively. The estimated 4-year OS rate for group 5 patients was 83.6% compared with 44.8% for historical control data.
Relapsed/refractory Ph+ ALL
Imatinib monotherapy was available for efficacy evaluation in 66 of 429 patients with relapsed/refractory Ph+ ALL, resulting in a hematologic response in 33% (complete response in 12%) and a major cytogenetic response in 23% (note that 353 of the 429 patients were part of the expanded study and no primary efficacy data were collected). The median time to disease progression was 1.9-3.1 months in all 429 patients; of these, 409 evaluable patients had a median survival time of 5-9 months. 14 patients received imatinib + induction chemotherapy regimens, 92% of 12 evaluable patients achieved a complete hematologic response, and 100% of 8 evaluable patients achieved a major cytogenetic response. 4 patients underwent molecular Molecular genetic evaluation was performed in 4 patients, and complete responses were obtained in 2 cases.
Due to the lack of a radical regimen, 146 relapsed/resistant patients aged 55 years or older received imatinib monotherapy and were analyzed separately. Of these, 14 received a therapeutic dose of imatinib 600 mg/day, with 5 (35%) patients achieving a complete hematologic response and 7 (50%) patients achieving a major cytogenetic response. Of note, four patients treated with imatinib at a reduced dose (400 mg/day) did not respond, indicating that this treatment dose was inadequate. The median disease-free survival time for all 146 patients was 2.8-3.1 months, with a median overall survival of 7.4-8.9 months.
Clinical studies of HES/CEL
In an open, multicenter phase II clinical study (B2225) examining the efficacy and safety of imatinib mesylate in the treatment of life-threatening diseases associated with ABL, Kit or PDGFR protein tyrosine kinases. The study included 14 patients with eosinophilic excess syndrome/chronic eosinophilic leukemia (HES/CEL), ranging in age from 16 to 64 years, treated with imatinib mesylate at 100 mg to 1000 mg daily. In 35 additional published case reports, 162 patients with HES/CEL aged 11 to 78 years treated with imatinib mesylate at doses ranging from 75 mg to 800 mg daily were reported, and hematologic response rates are shown in the table below. The duration of response in patients reported in the literature ranged from 6+ weeks to 44 months.
Response rates for HES/CEL
Cytogenetic abnormalities
Number of Patients
Complete hematologic response
Partial hematologic response
  N (%) N (%) Positive FIP1L1-PDGFRα fusion kinase
61 61 (100%) 0% Negative FIP1L1-PDGFRα fusion kinase
56 12 (21%) 9 (16%) Unknown cytogenetic abnormality
59 34 (58%) 7 (12%) Total
176 107 (61%) 23 (13%) Clinical studies in MDS/MPD
In an open, multicenter phase II clinical study (B2225) examining the efficacy and safety of imatinib mesylate in the treatment of life-threatening diseases associated with ABL, Kit, or PDGFR protein tyrosine kinases. This study included seven patients with myelodysplastic syndromes/myeloproliferative disorders (MDS/MPD). These patients were treated with imatinib mesylate 400 mg daily and the patients’ age range was 20 to 86 years. An additional 24 patients with MDS/MPD, ranging in age from 2 to 79 years, were reported in 12 published case reports and one clinical study, and received imatinib mesylate at a dose of 400 mg daily, except for 3 patients who received lower doses (100 mg/200 mg/300 mg). Of the total 31 treated patients with MDS/MPD, 14 patients (45%) achieved a complete hematologic response and 9 patients (29%) achieved a complete cytogenetic response (39% achieved a major and partial cytogenetic response). It should be noted that 14 evaluable patients had chromosomal translocations, including chromosome 5q33 or 4q12, causing PDGFR gene rearrangements. All of these patients achieved a hematologic response (12 achieved a complete response). 11 of the 14 patients were evaluated for cytogenetic response, and all 11 patients achieved a response (9 achieved a complete response). Of the 16 patients in whom chromosomal translocations and PDGFR gene rearrangements were not detected, only 2 (13%) achieved a complete hematologic response and 1 (6%) achieved a major cytogenetic response. Another patient with PDGFR gene rearrangement and molecular genetic relapse after bone marrow transplantation again achieved a molecular genetic response. The median duration of treatment for the seven patients treated in the phase II study was 12.9 months (0.8 to 26.7), and in the published literature the median duration of treatment for patients who responded ranged from 1 week to more than 18 months, as shown in the table below. The duration of response in phase II studies ranged from 141+ days to 457+ days.
Response rates in MDS/MPD
  Complete hematologic response Major cytogenetic response NN (%) N (%) Total population31 14 (45) 12 (39) Chromosome 5 translocation14 11 (79) 11 (79) Chromosome 4 translocation2 2 (100) 1 (50) Other/no translocation14 1 (7) 0 (0) Relapse at the molecular level1 NE1NE11 NE: not assessable   
 Clinical studies of ASM
In an open, multicenter phase II clinical study (B2225) examining the efficacy and safety of imatinib mesylate for the treatment of life-threatening diseases associated with ABL, Kit, or PDGFR protein tyrosine kinases. This study included five patients with aggressive systemic mastocytic hyperplasia (ASM) who received imatinib mesylate at doses ranging from 100 mg to 400 mg daily and an age range of 49 to 74 years. Another 10 published case reports reported 23 patients with ASM aged 26 to 85 years who received imatinib mesylate at doses ranging from 100 mg to 400 mg daily.
In the published case reports and in the phase II study, 20 of the 28 patients with ASM were evaluated for cytogenetic abnormalities. 7 of the 20 patients had FIP1L1-PDGFRα fusion kinase (or CHIC2 deletion). Two patients had Kit mutations in the proximal membrane region (1 Phe522Cys and 1 K509I), 4 patients had D816V c-Kit mutations (considered insensitive to imatinib mesylate), and 1 patient had concurrent CML.
Of the 28 treated ASM patients, 8 patients (29%) achieved a complete hematologic response and 9 patients (32%) achieved a partial hematologic response (63% overall response rate). In the phase II study, the median duration of treatment with imatinib mesylate in the 5 patients with ASM was 13 months (range 1.4 to 22.3 months), and this median duration ranged from 1 month to more than 30 months in patients who experienced a response as reported in the published medical literature.The response rates of patients with ASM to imatinib mesylate are shown in the table below. The duration of response for patients in the literature ranges from 1 month to more than 30 months.
Response rates for ASM
Number of patients with cytogenetic abnormalities Complete hematologic response Partial hematologic response N (%) N (%) FIP1L1-PDGFRα fusion kinase (or CHIC2 deletion)8 80 Mutation in proximal membrane region2 0 2 Unknown or no cytogenetic abnormality deletion16 17 D816V mutation4 1* 0 Total 30 10 (33%)9 (30%)* Concurrent CML and ASM Patients For systemic mastocytosis (SM), which is less aggressive, imatinib mesylate has not been shown to be effective. Therefore, imatinib mesylate is not recommended for cutaneous mastocytosis, quiescent systemic mastocytosis (occult SM or simple myeloid mastocytosis), SM with associated clonal blood-based non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma, or extracutaneous mast cell tumors. Patients with the D816V c-Kit mutation are not sensitive to imatinib mesylate and should not be treated with imatinib mesylate.
Clinical studies of DFSP
Dorsal fibrosarcoma of the bulge (DFSP) is a soft tissue sarcoma of the skin. It is characterized by a translocation of chromosomes 17 and 22, causing a fusion of the α1 type I collagen gene and the PDGF B gene.
In an open, multicenter phase II clinical study (B2225), the efficacy and safety of imatinib mesylate for the treatment of life-threatening disease associated with ABL, Kit, or PDGFR protein tyrosine kinases was examined. This study enrolled 12 patients with metastatic DFSP who had local recurrence after initial surgical resection and for whom further surgery did not provide clinical benefit. They were treated with imatinib mesylate 800 mg daily (age range 23 to 75 years). An additional 6 patients with DFSP treated with imatinib mesylate, with an age range of 18 months to 49 years, were reported in 5 published case reports. Thus, a total of 18 patients with DFSP were treated with imatinib mesylate, 8 of whom had metastatic disease. In the published literature, adult patients were treated with either 400 mg/day (4 cases) or 800 mg/day (1 case) of imatinib mesylate. One pediatric patient received 400 mg/m2/day and subsequently increased to 520 mg/m2/day. 10 patients had PDGF B gene rearrangements, 5 patients had no available cytogenetic data, and 3 patients had complex cytogenetic abnormalities. The response to treatment is shown in the table below.
Response rate of DFSP
Number of patients with tumor response (n=18) % Complete response 7 39 Partial response* 8 44 Total response 15 83 * 5 patients achieved disease free survival by surgery 12 of these 18 patients either achieved complete response (7 patients) or disease free survival by surgery after partial response (5 patients, including 1 child), bringing the total complete response rate to 67%. Another 3 patients achieved partial response, bringing the overall response rate to 83%. Of the 8 patients with metastatic disease, 5 patients showed a response (62%), including 3 patients with a complete response (37%). Of the 10 patients with PDGF B gene rearrangements, 4 had a complete response and 6 had a partial response. The median duration of treatment in the phase II study was 6.2 months and the maximum duration was 24.3 months, while in the published literature this duration ranges from 4 weeks to more than 20 months.
Clinical studies in patients with hepatic insufficiency
In a trial of patients with varying degrees of hepatic insufficiency (mild, moderate and severe), mean imatinib exposure (standard dose AUC) was not increased compared to patients with normal liver function. In this study, 500 mg once daily was safe in patients with mild hepatic insufficiency, and 300 mg once daily was safe in other patients with hepatic insufficiency. Although only 300 mg once daily was used in patients with moderate to severe hepatic insufficiency, pharmacokinetic analysis showed that 400 mg was also safe at this dose level (see Dosage, Precautions, Adverse Reactions, Pharmacokinetics).
Clinical studies in patients with renal insufficiency
In a trial of patients with varying degrees of renal insufficiency (mild, moderate, and severe), mean imatinib exposure (standard dose AUC) increased 1.5-2 fold compared to patients with normal renal function, consistent with increased levels of plasma AGP, a protein that binds strongly to imatinib. A correlation between imatinib exposure and the severity of renal insufficiency has not been found. In this study, 800 mg once daily was safe in patients with mild renal insufficiency, and 600 mg once daily was safe in patients with moderate renal insufficiency. Due to the limited number of patients included in the trial, the 800 mg dose level has not been studied in patients with moderate renal insufficiency. Only two patients with severe renal insufficiency were included in the study and received the low dose (100 mg); no higher doses were evaluated. Patients undergoing hemodialysis were not included in the study. Literature data suggest that a patient with end-stage renal disease undergoing hemodialysis tolerated this dose of 400 mg well. This patient’s PK plasma exposure fell within the range of normal renal function for imatinib and its metabolite CGP74588, and dialysis has not been found to affect the plasma kinetics of imatinib. Because imatinib is barely excreted by the kidneys, patients with severe renal insufficiency and those on dialysis may receive a starting dose of 400 mg. However, caution is still required in these patients. If not tolerated, the dose may be reduced; for poor efficacy, the dose may be increased (see [Dosage], [Precautions], [Pharmacokinetics]).
Pharmacology and Toxicology
Pharmacological effects
Mechanism of action
Imatinib is a small molecule protein tyrosine kinase inhibitor that effectively inhibits the activity of BCR-ABL tyrosine kinase (TK) and several TK receptors: Kit, stem cell factor (SCF) receptor encoded by the c-Kit proto-oncogene, discoid domain receptors (DDR1 and DDR2), colony-stimulating factor receptor (CSF-1R), and platelet-derived growth factor receptors α and β (PDGFR-α and PDGFR-β). Imatinib also inhibits cellular behavior mediated by activation of these receptor kinases.
Imatinib inhibits BCR-ABL tyrosine kinase at the cellular level both in vitro and in vivo, and selectively inhibits proliferation and induces apoptosis in fresh cells from BCR-ABL-positive cell lines, Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) and acute lymphoblastic leukemia patients.
In addition, imatinib inhibits platelet-derived growth factor (PDGF) receptor, stem cell factor (SCF), and tyrosine kinase of the c-Kit receptor, thereby inhibiting cellular behavior mediated by PDGF and stem cell factor.
Gastrointestinal mesenchymal tumor (GIST) cells express active Kit mutations, and in vitro experiments have shown that imatinib inhibits the proliferation and induces apoptosis in GIST cells.
There are very few reports of the development of resistance in the clinic, and with regard to the development of imatinib resistance, the difference between initial resistance (ineffective from the start of treatment) and secondary resistance is the molecular mechanism of resistance development by showing ineffectiveness throughout the course of imatinib exposure and BCR-ABL tyrosine kinase, which increases over the course of the disease. Drug resistance has been observed to occur in patients taking low doses or not taking the drug regularly. Therefore, treatment should be initiated as early as possible and the dose should be strictly as required.
Toxicological studies
Following long-term treatment with imatinib, there was an increased incidence of opportunistic infections in rats and an exacerbation of normally suppressed malaria infections in monkeys.
Genotoxicity
Imatinib did not show any genotoxic properties in an in vitro bacterial (Ames test) assay, an in vitro mammalian cell analysis (mouse lymphoma assay), or an in vivo rat micronucleus assay. In an in vitro mammalian cell gene fragmentation (clastogenicity) assay
(chromosomal aberrations in Chinese gopher ovary cells), imatinib was found to have a positive genotoxic effect when metabolism was activated. Two intermediates that were present in the finished product as a result of the manufacturing process were shown to be mutagenic in the Ames assay, and one of the intermediates was also positive in a mouse lymphoma assay.
Reproductive toxicity
In a fertility assay, male rats given 60 mg/kg (approximately equivalent to a maximum clinical dose of 800 mg/day) for 70 consecutive days showed a reduction in testicular and paratesticular weight, as well as a reduction in sperm motility. A mild to moderate reduction in sperm production was also observed in dogs at an oral dose of >30 mg/kg. In a fertility study in female rats, the number of mated and pregnant rats did not change, but at doses of 60 mg/kg rather than ≤20 mg/kg, there was a significant increase in post-implantation fetal mortality along with a decrease in the number of live fetuses.
In a perinatal developmental study in rats given 45 mg/kg/day orally, there was an increase in the number of stillbirths and deaths between postnatal day 0 and day 4. the mean body weight of F1 generation littermates given the same dose was reduced from birth to endpoint autopsy. the fertility of the F1 generation was not affected, but an increase in the number of absorbed fetuses was noted in the 45 mg/kg/day dose group.
The number of fetuses able to bear children was also reduced. The maternal animals were given 45 mg/kg/day and the F1 generation was given 15 mg/kg/day (¼ of the maximum clinical dose of 800 mg), a dose level with no toxic effects.
Imatinib ≥100 mg/kg given to rats during the organogenesis phase was teratogenic, a dose equivalent to approximately 1.5 times the clinical maximum dose of 800 mg/day. Teratogenic effects included dewlap and brain bulge, as well as absent/deficient frontal bones and/or absent parietal bones. These effects were not observed in the ≤30 mg/kg group.
Experiments in rats have demonstrated embryotoxic and teratogenic effects of imatinib. Although reduced testicular and epididymal weights and reduced numbers of motile spermatozoa were observed in high-dose male rats, fertility was not affected in preclinical fertility and early embryonic development studies. Fertility in F1 generation littermates was also unaffected by Gleevec in preclinical pre- and postnatal studies in rats.
No new target organ damage was observed in toxicology studies observing growth and development in young rats (10-70 days postnatal). In other juvenile animal toxicology studies, a transient effect on growth and delayed vaginal opening and foreskin separation was observed at approximately 0.3-2 times the mean pediatric exposure dose. Also, mortality in young animals (weaning stage) was observed at approximately 2 times the mean pediatric exposure dose. The maximum recommended pediatric doses above are all 340 mg/m2 .
 Carcinogenicity
In a 2-year rat carcinogenicity study, imatinib was administered at regimens of 15, 30 and 60 mg/kg/day, resulting in a statistically significant reduction in life expectancy in male rats in the 60 mg/kg/day group and in females in the ≥30 mg/kg/day group, showing statistically significant significance. Histopathological findings of the deceased rats indicated cardiomyopathy (males and females), chronic progressive nephropathy (females) and foreskin gland papilloma as the main causes of death. Target organs showing tumor changes were the kidney, bladder, urethra, prepuce and clitoral glands, small intestine, parathyroid glands, adrenal glands, and the eglandular region of the stomach. The doses at which no observed effect levels (NOEL) were observed in target organs with tumor damage were 30 mg/kg/day in the kidney, bladder, urethra, small intestine, parathyroid glands, adrenal glands, and eglandular region of the stomach, and 15 mg/kg/day in the prepuce and clitoral glands.
The incidence of prepuce gland/papilloma/carcinoma was more pronounced at dose levels of 30 and 60 mg/kg/day, corresponding to 0.5 to 4 or 0.3 to 2.4 times the human daily exposure at dose levels of 400 mg/day or 800 mg/day (as evaluated by AUC), while the dose level of 340 mg/m2 corresponds to 0.4 to 3.0 times the daily exposure in children (as evaluated by AUC) At a dose level of 60 mg/kg/day, adenomas/carcinomas of the kidney, papillomas of the bladder and urethra, adenocarcinomas of the small intestine, parathyroid adenomas, benign and malignant medullary tumors of the adrenal glands, and papillomas/carcinomas of the eglandular stomach were susceptible.
The relevance of the above findings of carcinogenicity in rats to humans is currently unknown. Analysis of safety data from clinical trials and spontaneous adverse event reports has not demonstrated a higher incidence of malignancy in patients treated with imatinib than in the general population.
Non-tumor damage to the cardiovascular system, pancreas, endocrine organs, and teeth has not been demonstrated in early preclinical trials. In some animals, the most important signs causing cardiac insufficiency include myocardial hypertrophy and cardiac enlargement.
[Pharmacokinetics].
The pharmacokinetics of imatinib was evaluated in the dose range of 25~1000 mg, at a single dose and after reaching steady state.
The increase in the mean area under the curve (AUC) of imatinib doses in the range of 25 to 1000 mg was proportional to the dose. Repeated dosing resulted in drug accumulation of 1.5 to 2.5 times at the time of reaching steady state.
Absorption
The mean absolute bioavailability of imatinib was 98%, and the coefficient of variation of plasma imatinib AUC after oral administration fluctuated between 40% and 60%. The absorption of this drug was slightly reduced after a high-fat diet (11% reduction in Cmax and 1.5 hours delay in tmax) and the AUC was slightly reduced (7.4%) compared with that during fasting.
Distribution
Approximately 95% is bound to plasma proteins, the majority to albumin, a small proportion to alpha-acidic glycoproteins, and only a very small proportion to lipoproteins. The overall distribution concentration in the whole body is high, with a distribution volume of 4.9 L/kg body weight, but the distribution ratio in erythrocytes is low. The distribution of the drug in body tissues is based on preclinical data only. Uptake levels were high in the adrenal glands and gonads and low in the central nervous system.
Metabolism
The major circulating metabolite in humans is the N-desmethylpiperazine derivative, which has similar potency to the prodrug in vitro. The plasma AUC of this metabolite is 16% of the AUC of the prodrug imatinib mesylate. Imatinib is a substrate of CYP3A4 and an inhibitor of CYP3A4, CYP2D6, CYP2C9 and CYP2C19, and therefore can affect the metabolism of the combination drug. (See [Drug Interactions]).
 Elimination
Imatinib has an elimination half-life of 18 hours and a half-life of 40 hours for its active metabolites. Approximately 81% of the administered drug dose is excreted over 7 days, with 68% excreted in the feces and 13% excreted in the urine. About 25% is the prodrug (5% in urine and 20% in stool) and the rest are metabolites, with similar proportions of active metabolites and prodrugs in feces and urine.
Pharmacokinetics in specific patient populations
Pharmacokinetic studies in adult populations have shown that gender has no effect on pharmacokinetics and that the effect of body weight can be omitted.
Given the same dose (400 mg/day), the steady-state drug exposure in GIST patients is 1.5 times higher than that in CML patients.
Based on preliminary population pharmacokinetic studies in GIST patients, there were three changes in the pharmacokinetics of imatinib (albumin, WBC, and bilirubin) that had statistically significant effects.
Low albumin levels reduced clearance, as did higher WBC levels. However, these effects are not sufficient to conclude that dose adjustment is required.
Pediatric Dosing
Doses of 260 mg/m2 and 340 mg/m2 used in children and adolescents produce the same drug exposure, equivalent to 400 mg and 600 mg in adults, respectively. after repeated dosing at 340 mg/m2/day via once-daily dosing, the AUC (0-24) ratio on day 8 and day 1 reveals a 1.7-fold drug accumulation.
Geriatric dosing
No significant effect of age on pharmacokinetics was reported in the results of a clinical study in >20% of patients over 65 years of age.
Organ insufficiency
Imatinib and its metabolites are barely excreted through the kidneys. Plasma exposure is slightly higher in patients with mild to moderate renal insufficiency than in patients with normal renal function, with an increase of approximately 1.5 to 2-fold, consistent with a 1.5-fold increase in plasma AGP levels, which are firmly bound to imatinib. Since imatinib is barely excreted by the kidneys, imatinib prodrug clearance is presumably similar in patients with renal insufficiency and normal renal function (see [DOSAGE AND ADMINISTRATION], [PRECAUTIONS]).
Although pharmacokinetic results showed individual differences, no increase in mean exposure to imatinib was observed in patients with varying degrees of hepatic insufficiency compared to patients with normal hepatic function (see [Dosage], [Precautions], [Adverse Reactions]).
 Storage
Store below 30°C.
 Packaging
PVC-aluminum blister pack, 60 tablets/box

 Expiration date
36 months.
 Executive Standard
Imported drug registration standard: JX20140149
 [Imported drug registration certificate number
H20150112
 Manufacturer
Company Name: Novartis Pharma Schweiz AG
Production
Production
Plant: Novartis Pharma Produktions GmbH
Production Address: Oeflingerstrasse 44,79664 Wehr,Germany
 Contact address: No. 31 Yongan Road, Changping District, Beijing
Postal code: 102200
Phone number: 400 818 0600, 800 990 0016
800 990 0016
Fax number: 010-6505 7099
Web
Address: www. novartis.com.cn