10??????????OVERDOSAGE Experience with doses greater than 800 mg is limited. Isolated cases of Gleevec overdose have been reported. In the event of overdosage, the patient should be observed and appropriate supportive treatment given. Adult Overdose 1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days): Weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain. 6,400 mg (single dose): One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases. 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported. A patient with myeloid blast crisis experienced Grade 1 elevations of serum creatinine, Grade 2 ascites and elevated liver transaminase levels, and Grade 3 elevations of bilirubin after inadvertently taking 1,200 mg of Gleevec daily for 6 days. Therapy was temporarily interrupted and complete reversal of all abnormalities occurred within 1 week. Treatment was resumed at a dose of 400 mg daily without recurrence of adverse reactions. Another patient developed severe muscle cramps after taking 1,600 mg of Gleevec daily for 6 days. Complete resolution of muscle cramps occurred following interruption of therapy and treatment was subsequently resumed. Another patient that was prescribed 400 mg daily, took 800 mg of Gleevec on Day 1 and 1,200 mg on Day 2. Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy. Pediatric Overdose One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhea and anorexia and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhea.
STORAGE AND HANDLING SECTION.
Storage and Handling Store at 25??C (77??F); excursions permitted to 15??C-30??C (59??F-86??F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight container, USP. Gleevec is an antineoplastic product. Follow special handling and disposal procedures1 Gleevec tablets should not be crushed. Direct contact of crushed tablets with the skin or mucous membranes should be avoided. If such contact occurs, wash thoroughly as outlined in the references. Personnel should avoid exposure to crushed tablets.
WARNINGS AND PRECAUTIONS SECTION.
5??????????WARNINGS AND PRECAUTIONS Edema and severe fluid retention have occurred. Weigh patients regularly and manage unexpected rapid weight gain by drug interruption and diuretics (5.1, 6.1, 6.9) Cytopenias, particularly anemia, neutropenia, and thrombocytopenia, have occurred. Manage with dose reduction or dose interruption and in rare cases discontinuation of treatment. Perform complete blood counts weekly for the first month, biweekly for the second month, and periodically thereafter (5.2) Severe congestive heart failure and left ventricular dysfunction have been reported, particularly in patients with comorbidities and risk factors. Patients with cardiac disease or risk factors for cardiac failure should be monitored and treated (5.3) Severe hepatotoxicity including fatalities may occur. Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated. Monitor liver function when combined with chemotherapy known to be associated with liver dysfunction (5.4) Grade 3/4 hemorrhage has been reported in clinical studies in patients with newly diagnosed CML and with GIST. GI tumor sites may be the source of GI bleeds in GIST (5.5) Gastrointestinal perforations, some fatal, have been reported (5.6) Cardiogenic shock/left ventricular dysfunction has been associated with the initiation of Gleevec in patients with conditions associated with high eosinophil levels (e.g., HES, MDS/MPD and ASM) (5.7) Bullous dermatologic reactions (e.g., erythema multiforme and Stevens-Johnson syndrome) have been reported with the use of Gleevec (5.8) Hypothyroidism has been reported in thyroidectomy patients undergoing levothyroxine replacement. Closely monitor TSH levels in such patients (5.9) Fetal harm can occur when administered to a pregnant woman. Women should be apprised of the potential harm to the fetus (5.10, 8.1) Growth retardation occurring in children and pre-adolescents receiving Gleevec has been reported. Close monitoring of growth in children under Gleevec treatment is recommended (5.11, 6.11) Tumor lysis syndrome. Close monitoring is recommended (5.12) Reports of motor vehicle accidents have been received in patients receiving Gleevec. Caution patients about driving a car or operating machinery (5.13) 5.1??????????Fluid Retention and Edema Gleevec is often associated with edema and occasionally serious fluid retention [see Adverse Reactions (6.1)]. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher Gleevec dose and age >65 years in the CML studies. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking Gleevec, and in 2%-6% of other adult CML patients taking Gleevec. In addition, other severe fluid retention (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) reactions were reported in 1.3% of newly diagnosed CML patients taking Gleevec, and in 2%???6% of other adult CML patients taking Gleevec. Severe fluid retention was reported in 9% to 13.1% of patients taking Gleevec for GIST [see Adverse Reactions (6.9)]. In a randomized trial in patients with newly diagnosed Ph+CML in chronic phase comparing Gleevec and nilotinib, severe (Grade 3 or 4) fluid retention occurred in 2.5% of patients receiving Gleevec and in 3.9% of patients receiving nilotinib 300 mg bid. Effusions (including pleural effusion, pericardial effusion, ascites) or pulmonary edema were observed in 2.1% (none were Grade 3 or 4) of patients in the Gleevec arm and 2.2% (0.7% Grade 3 or 4) of patients in the nilotinib 300 mg bid arm. 5.2??????????Hematologic Toxicity Treatment with Gleevec is associated with anemia, neutropenia, and thrombocytopenia. Complete blood counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter as clinically indicated (for example, every 2-3 months). In CML, the occurrence of these cytopenias is dependent on the stage of disease and is more frequent in patients with accelerated phase CML or blast crisis than in patients with chronic phase CML. In pediatric CML patients the most frequent toxicities observed were Grade 3 or 4 cytopenias including neutropenia, thrombocytopenia and anemia. These generally occur within the first several months of therapy [see Dosage and Administration (2.12)]. 5.3??????????Congestive Heart Failure and Left Ventricular Dysfunction Congestive heart failure and left ventricular dysfunction have been reported in patients taking Gleevec. Most of the patients with reported cardiac reactions have had other co-morbidities and risk factors, including advanced age and previous medical history of cardiac disease. In an international randomized phase 3 study in 1,106 patients with newly diagnosed Ph+ CML in chronic phase, severe cardiac failure and left ventricular dysfunction were observed in 0.7% of patients taking Gleevec compared to 0.9% of patients taking IFN + Ara-C. In another randomized trial with newly diagnosed Ph+ CML patients in chronic phase that compared Gleevec and nilotinib, cardiac failure was observed in 1.1% of patient in the Gleevec arm and 2.2% of patients in the nilotinib 300 mg bid arm and severe (Grade 3 or 4) cardiac failure occurred in 0.7% of patients in each group. Patients with cardiac disease or risk factors for cardiac or history of renal failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated. 5.4??????????Hepatotoxicity Hepatotoxicity, occasionally severe, may occur with Gleevec [see Adverse Reactions (6.1)]. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of Gleevec. Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly, or as clinically indicated. Laboratory abnormalities should be managed with Gleevec interruption and/or dose reduction [see Dosage and Administration (2.12)]. When Gleevec is combined with chemotherapy, liver toxicity in the form of transaminase elevation and hyperbilirubinemia has been observed. Additionally, there have been reports of acute liver failure. Monitoring of hepatic function is recommended. 5.5??????????Hemorrhage In a trial of Gleevec versus IFN+Ara-C in patients with the newly diagnosed CML, 1.8% of patients had Grade 3/4 hemorrhage. In the Phase 3 unresectable or metastatic GIST studies, 211 patients (12.9%) reported Grade 3/4 hemorrhage at any site. In the Phase 2 unresectable or metastatic GIST study, 7 patients (5%) had a total of 8 CTC Grade 3/4 hemorrhages; gastrointestinal (GI) (3 patients), intra-tumoral (3 patients) or both (1 patient). Gastrointestinal tumor sites may have been the source of GI hemorrhages. In a randomized trial in patients with newly diagnosed Ph+ CML in chronic phase comparing Gleevec and nilotinib, GI hemorrhage occurred in 1.4% of patients in the Gleevec arm, and in 2.9% of patients in the nilotinib 300 mg bid arm. None of these events were Grade 3 or 4 in the Gleevec arm; 0.7% were Grade 3 or 4 in the nilotinib 300 mg bid arm. In addition, gastric antral vascular ectasia has been reported in postmarketing experience. 5.6??????????Gastrointestinal Disorders Gleevec is sometimes associated with GI irritation. Gleevec should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including fatalities, of gastrointestinal perforation. 5.7??????????Hypereosinophilic Cardiac Toxicity In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of Gleevec therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding Gleevec. Myelodysplastic/myeloproliferative disease and systemic mastocytosis may be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL, and in patients with MDS/MPD or ASM associated with high eosinophil levels. If either is abnormal, the prophylactic use of systemic steroids (1-2 mg/kg) for one to two weeks concomitantly with Gleevec should be considered at the initiation of therapy. 5.8??????????Dermatologic Toxicities Bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome, have been reported with use of Gleevec. In some cases of bullous dermatologic reactions, including erythema multiforme and Stevens-Johnson syndrome reported during postmarketing surveillance, a recurrent dermatologic reaction was observed upon rechallenge. Several foreign postmarketing reports have described cases in which patients tolerated the reintroduction of Gleevec therapy after resolution or improvement of the bullous reaction. In these instances, Gleevec was resumed at a dose lower than that at which the reaction occurred and some patients also received concomitant treatment with corticosteroids or antihistamines. 5.9??????????Hypothyroidism Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with Gleevec. TSH levels should be closely monitored in such patients. 5.10??????????Embryo-fetal Toxicity Gleevec can cause fetal harm when administered to a pregnant woman. Imatinib mesylate was teratogenic in rats when administered during organogenesis at doses approximately equal to the maximum human dose of 800 mg/day based on body surface area. Significant post-implantation loss was seen in female rats administered imatinib mesylate at doses approximately one-half the maximum human dose of 800 mg/day based on body surface area. Sexually active female patients of reproductive potential taking Gleevec should use highly effective contraception. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 5.11??????????Children and Adolescents Growth retardation has been reported in children and pre-adolescents receiving Gleevec. The long term effects of prolonged treatment with Gleevec on growth in children are unknown. Therefore, close monitoring of growth in children under Gleevec treatment is recommended [see Adverse Reactions (6.11)]. 5.12??????????Tumor Lysis Syndrome Cases of Tumor Lysis Syndrome (TLS), including fatal cases, have been reported in patients with CML, GIST, ALL and eosinophilic leukemia receiving Gleevec. The patients at risk of TLS are those with tumors having a high proliferative rate or high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Due to possible occurrence of TLS, correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of Gleevec.?? 5.13??????????Driving and Using Machinery Reports of motor vehicle accidents have been received in patients receiving Gleevec. While most of these reports are not suspected to be caused by Gleevec, patients should be advised that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with Gleevec. Therefore, caution should be recommended when driving a car or operating machinery.
DRUG INTERACTIONS SECTION.
7??????????DRUG INTERACTIONS CYP3A4 inducers may decrease Gleevec Cmax and AUC (2.11, 7.1) CYP3A4 inhibitors may increase Gleevec Cmax and AUC (7.2) Gleevec is an inhibitor of CYP3A4 and CYP2D6 which may increase the Cmax and AUC of other drugs (7.3, 7.4) Patients who require anticoagulation should receive low-molecular weight or standard heparin and not warfarin (7.3) 7.1??????????Agents Inducing CYP3A Metabolism Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of Gleevec, increased Gleevec oral-dose clearance by 3.8-fold, which significantly (p400 mg/day or the chronic use of concomitant acetaminophen and Gleevec.
NONCLINICAL TOXICOLOGY SECTION.
13??????????NONCLINICAL TOXICOLOGY 13.1??????????Carcinogenesis, Mutagenesis, Impairment of Fertility In the 2-year rat carcinogenicity study administration of imatinib at 15, 30, and 60 mg/kg/day resulted in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at ???30 mg/kg/day. Target organs for neoplastic changes were the kidneys (renal tubule and renal pelvis), urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-glandular stomach. Neoplastic lesions were not seen at: 30 mg/kg/day for the kidneys, urinary bladder, urethra, small intestine, parathyroid glands, adrenal glands and non-glandular stomach, and 15 mg/kg/day for the preputial and clitoral gland. The papilloma/carcinoma of the preputial/clitoral gland were noted at 30 and 60 mg/kg/day, representing approximately 0.5 to 4 or 0.3 to 2.4 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, respectively, and 0.4 to 3.0 times the daily exposure in children (based on AUC) at 340 mg/m2. The renal tubule adenoma/carcinoma, renal pelvis transitional cell neoplasms, the urinary bladder and urethra transitional cell papillomas, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and malignant medullary tumors of the adrenal glands and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day. The relevance of these findings in the rat carcinogenicity study for humans is not known. Positive genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates of the manufacturing process, which are also present in the final product, are positive for mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma assay. Imatinib was not genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus assay. In a study of fertility, male rats were dosed for 70 days prior to mating and female rats were dosed 14 days prior to mating and through to gestational Day 6. Testicular and epididymal weights and percent motile sperm were decreased at 60 mg/kg, approximately three-fourths the maximum clinical dose of 800 mg/day based on body surface area. This was not seen at doses ???20 mg/kg (one-fourth the maximum human dose of 800 mg). The fertility of male and female rats was not affected. In a pre- and postnatal development study in female rats dosed with imatinib mesylate at 45 mg/kg (approximately one-half the maximum human dose of 800 mg/day, based on body surface area) from gestational Day 6 until the end of lactation, red vaginal discharge was noted on either gestational Day 14 or 15. In the first generation offspring at this same dose level, mean body weights were reduced from birth until terminal sacrifice. First generation offspring fertility was not affected but reproductive effects were noted at 45 mg/kg/day including an increased number of resorptions and a decreased number of viable fetuses. Fertility was not affected in the preclinical fertility and early embryonic development study although lower testes and epididymal weights as well as a reduced number of motile sperm were observed in the high dose males rats. In the preclinical pre- and postnatal study in rats, fertility in the first generation offspring was also not affected by Gleevec. Human studies on male patients receiving Gleevec and its affect on male fertility and spermatogenesis have not been performed. Male patients concerned about their fertility on Gleevec treatment should consult with their physician. 13.2??????????Animal Toxicology and/or Pharmacology Toxicities from Long-Term Use It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney, and cardiac toxicity and immunosuppression. Severe liver toxicity was observed in dogs treated for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia. Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralization and dilation of the renal tubules and tubular nephrosis. Increased BUN and creatinine were observed in several of these animals. An increased rate of opportunistic infections was observed with chronic imatinib treatment in laboratory animal studies. In a 39 week monkey study, treatment with imatinib resulted in worsening of normally suppressed malarial infections in these animals. Lymphopenia was observed in animals (as in humans). Additional long-term toxicities were identified in a 2-year rat study. Histopathological examination of the treated rats that died on study revealed cardiomyopathy (both sexes), chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Non-neoplastic lesions seen in this 2-year study which were not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals.
USE IN SPECIFIC POPULATIONS SECTION.
8??????????USE IN SPECIFIC POPULATIONS There is no experience in children less than 1 year of age (8.4) Pregnancy: Sexually active female patients should use highly effective contraception during treatment (5.10) 8.1??????????Pregnancy Pregnancy Category D [see Warnings and Precautions (5.10)]. Risk Summary Gleevec can cause fetal harm when administered to a pregnant woman. There have been postmarket reports of spontaneous abortions and infant congenital anomalies from women who have taken Gleevec. Imatinib was teratogenic in animals. Women should be advised not to become pregnant when taking Gleevec. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Animal Data Imatinib mesylate was teratogenic in rats when administered orally during organogenesis at doses ???100 mg/kg (approximately equal to the maximum human dose of 800 mg/day based on body surface area). Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal bones. Female rats administered doses ???45 mg/kg (approximately one-half the maximum human dose of 800 mg/day based on body surface area) also experienced significant post-implantation loss as evidenced by early fetal resorption or stillbirths, nonviable pups and early pup mortality between postpartum Days 0 and 4. At doses higher than 100 mg/kg, total fetal loss was noted in all animals. Fetal loss was not seen at doses ???30 mg/kg (one-third the maximum human dose of 800 mg). 8.3??????????Nursing Mothers Imatinib and its active metabolite are excreted into human milk. Based on data from three breastfeeding women taking Gleevec, the milk: plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite. Considering the combined concentration of imatinib and active metabolite, a breastfed infant could receive up to 10% of the maternal therapeutic dose based on body weight. Because of the potential for serious adverse reactions in nursing infants from Gleevec, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4??????????Pediatric Use Gleevec safety and efficacy have been demonstrated in children with newly diagnosed Ph+ chronic phase CML and Ph+ ALL. There are no data in children under 1 year of age. As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients, with a Cmax of 2-4 hours. Apparent oral clearance was similar to adult values (11.0 L/hr/m2 in children vs. 10.0 L/hr/m2 in adults), as was the half-life (14.8 hours in children vs. 17.1 hours in adults). Dosing in children at both 260 mg/m2 and 340??mg/m2 achieved an AUC similar to the 400 mg dose in adults. The comparison of AUC on Day 8 vs. Day 1 at 260 mg/m2 and 340 mg/m2 dose levels revealed a 1.5- and 2.2-fold drug accumulation, respectively, after repeated once-daily dosing. Mean imatinib AUC did not increase proportionally with increasing dose. Based on pooled population pharmacokinetic analysis in pediatric patients with hematological disorders (CML, Ph+ ALL, or other hematological disorders treated with imatinib), clearance of imatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other demographics such as age, body weight and body mass index did not have clinically significant effects on the exposure of imatinib. The analysis confirmed that exposure of imatinib in pediatric patients receiving 260 mg/m2 once-daily (not exceeding 400 mg once-daily) or 340 mg/m2 once-daily (not exceeding 600 mg once-daily) were similar to those in adult patients who received imatinib 400 mg or 600 mg once-daily. 8.5??????????Geriatric Use In the CML clinical studies, approximately 20% of patients were older than 65 years. In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema [see Warnings and Precautions (5.1)]. The efficacy of Gleevec was similar in older and younger patients. In the unresectable or metastatic GIST study, 16% of patients were older than 65 years. No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis. In the adjuvant GIST study, 221 patients (31%) were older than 65 years. No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema.??The efficacy of Gleevec was similar in patients older than 65 years and younger patients. 8.6??????????Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 cancer patients with varying degrees of hepatic impairment (Table 16) at imatinib doses ranging from 100 mg-800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly and moderately hepatically-impaired groups and the normal group. Patients with severe hepatic impairment tend to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function. At steady state, the mean Cmax/dose and AUC/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function. The mean Cmax/dose and AUC/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function [see Dosage and Administration (2.11)]. Table 16 Liver Function Classification ULN=upper limit of normal for the institution Liver Function Test Normal (n=14) Mild (n=30) Moderate (n=20) Severe (n=20) Total Bilirubin ???ULN >1.0???1.5 times the ULN >1.5???3 times the ULN >3???10 times the ULN SGOT ???ULN >ULN (can be normal if Total Bilirubin is >ULN) Any Any 8.7??????????Renal Impairment The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 cancer patients with varying degrees of renal impairment (Table 17) at single and steady state imatinib doses ranging from 100 to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1.5- to 2-fold compared to patients with normal renal function. The AUCs did not increase for doses greater than 600 mg in patients with mild renal impairment. The AUCs did not increase for doses greater than 400 mg in patients with moderate renal impairment. Two patients with severe renal impairment were dosed with 100 mg/day and their exposures were similar to those seen in patients with normal renal function receiving 400 mg/day. Dose reductions are necessary for patients with moderate and severe renal impairment [see Dosage and Administration (2.11)]. Table 17 Renal Function Classification Renal Dysfunction Renal Function Tests Mild CrCL = 40-59 mL/min Moderate CrCL = 20-39 mL/min Severe CrCL = <20 mL/min CrCL = Creatinine Clearance
RECENT MAJOR CHANGES SECTION.
Warnings and Precautions (5)??????????1/2015
15??????????REFERENCES OSHA Hazardous Drugs. OSHA. [Accessed on 20-September- 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]
DOSAGE FORMS & STRENGTHS SECTION.
3??????????DOSAGE FORMS AND STRENGTHS 100 mg film coated tablets Very dark yellow to brownish orange, film-coated tablets, round, biconvex with bevelled edges, debossed with ???NVR??? on one side, and ???SA??? with score on the other side 400 mg film coated tablets Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with ???400??? on one side with score on the other side, and ???SL??? on each side of the score 400 mg film coated tablets Very dark yellow to brownish orange, film-coated tablets, ovaloid, biconvex with bevelled edges, debossed with ???gleevec??? on one side and score on the other side Tablets (scored): 100 mg and 400 mg (3)
ADVERSE REACTIONS SECTION.
6??????????ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The most frequently reported adverse reactions (>30%) were edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain (6.1, 6.9) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1??????????Chronic Myeloid Leukemia The majority of Gleevec-treated patients experienced adverse reactions at some time, most adverse reactions were of mild-to-moderate grade. Gleevec was discontinued due to drug-related adverse reactions in 2.4% of patients receiving Gleevec in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing Gleevec versus INF+Ara-C, and in 12.5% of patients receiving Gleevec in the randomized trial of newly diagnosed patients with Ph+ CML in chronic phase comparing Gleevec and nilotinib. Gleevec was discontinued due to drug-related adverse reactions in 4% of patients in chronic phase after failure of interferon-alpha therapy, in 4% of patients in accelerated phase and in 5% of patients in blast crisis. The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash (Table 2 and Table 3 for newly diagnosed CML, Table 4 for other CML patients). Edema was most frequently periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec [see Dosage and Administration (2.12)]. The frequency of severe superficial edema was 1.5%???6%. A variety of adverse reactions represent local or general fluid retention including pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema. These reactions appear to be dose related, were more common in the blast crisis and accelerated phase studies (where the dose was 600 mg/day), and are more common in the elderly. These reactions were usually managed by interrupting Gleevec treatment and using diuretics or other appropriate supportive care measures. A few of these reactions may be serious or life threatening, and one patient with blast crisis died with pleural effusion, congestive heart failure, and renal failure. Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the Gleevec treated patients are shown in Tables 2, 3, and 4. Table 2 Adverse Reactions Regardless of Relationship to Study Drug Reported in Newly Diagnosed CML Clinical Trial in the Gleevec versus INF+Ara-C Study (???10% of Gleevec Treated Patients)(1) (1)All adverse reactions occurring in ???10% of Gleevec treated patients are listed regardless of suspected relationship to treatment. (2)Other fluid retention reactions include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified. All Grades CTC Grades 3/4 Gleevec IFN+Ara???C Gleevec IFN+Ara???C Preferred Term N=551 (%) N=533 (%) N=551 (%) N=533 (%) Fluid Retention 61.7 11.1 2.5 0.9 ??? Superficial Edema 59.9 9.6 1.5 0.4 ??? Other Fluid Retention Reactions2 6.9 1.9 1.3 0.6 Nausea 49.5 61.5 1.3 5.1 Muscle Cramps 49.2 11.8 2.2 0.2 Musculoskeletal Pain 47.0 44.8 5.4 8.6 Diarrhea 45.4 43.3 3.3 3.2 Rash and Related Terms 40.1 26.1 2.9 2.4 Fatigue 38.8 67.0 1.8 25.1 Headache 37.0 43.3 0.5 3.8 Joint Pain 31.4 38.1 2.5 7.7 Abdominal Pain 36.5 25.9 4.2 3.9 Nasopharyngitis 30.5 8.8 0 0.4 Hemorrhage 28.9 21.2 1.8 1.7 - GI Hemorrhage 1.6 1.1 0.5 0.2 - CNS Hemorrhage 0.2 0.4 0 0.4 Myalgia 24.1 38.8 1.5 8.3 Vomiting 22.5 27.8 2.0 3.4 Dyspepsia 18.9 8.3 0 0.8 Cough 20.0 23.1 0.2 0.6 Pharyngolaryngeal Pain 18.1 11.4 0.2 0 Upper Respiratory Tract Infection 21.2 8.4 0.2 0.4 Dizziness 19.4 24.4 0.9 3.8 Pyrexia 17.8 42.6 0.9 3.0 Weight Increased 15.6 2.6 2.0 0.4 Insomnia 14.7 18.6 0 2.3 Depression 14.9 35.8 0.5 13.1 Influenza 13.8 6.2 0.2 0.2 Bone Pain 11.3 15.6 1.6 3.4 Constipation 11.4 14.4 0.7 0.2 Sinusitis 11.4 6.0 0.2 0.2 Table 3: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP in the Gleevec versus nilotinib Study (???10% in Gleevec 400 mg Once-Daily or nilotinib 300 mg Twice-Daily Groups) 60-Month Analysisa aExcluding laboratory abnormalities bNCI Common Terminology Criteria for Adverse Events, Version 3.0 Patients with Newly Diagnosed Ph+ CML-CP Gleevec 400 mg once-daily nilotinib 300 mg twice-daily Gleevec 400 mg once-daily nilotinib 300 mg twice-daily N=280 N=279 N=280 N=279 Body System and Preferred Term All Grades (%) CTC Gradesb 3/4 (%) Skin and subcutaneous tissue disorders Rash 19 38 2 3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10 x ULN), elevated alkaline phosphatase (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN), elevated SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN) Myeloid Blast Crisis (n=260) Accelerated Phase (n=235) Chronic Phase, IFN Failure (n=532) 600 mg n=223 400 mg n=37 600 mg n=158 400 mg n=77 400 mg % % % CTC Grades 1 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Hematology Parameters ??? Neutropenia 16 48 23 36 27 9 ??? Thrombocytopenia 30 33 31 13 21 5%) or in Cycles with Study Drug (>1%) * Defined as the frequency of AEs per patient per treatment cycles that included Gleevec (includes patients with Ph+ ALL that received cycles with Gleevec ** Defined as the frequency of AEs per patient per treatment cycles that did not include Gleevec (includes patients with Ph+ ALL that received cycles without Gleevec as well as all patients with Ph- ALL who did not receive Gleevec in any treatment cycle) Adverse Event Per Patient Incidence Ph+ALL With Gleevec N=92 n (%) Per Patient Incidence Ph- ALL No Gleevec N=65 n (%) Per Patient Per Cycle Incidence With Gleevec* N=778 n (%) Per Patient Per Cycle Incidence No Gleevec** N=647 n (%) Grade 3 and 4 Adverse Events Nausea and/or Vomiting 15 (16) 6 (9) 28 (4) 8 (1) Hypokalemia 31 (34) 16 (25) 72 (9) 32(5) Pneumonitis 7 (8) 1 (1) 7(1) 1(3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), N=12 CTC Grades1 Grade 3 % Grade 4 % Hematology Parameters - Anemia 17 0 - Thrombocytopenia 17 0 - Neutropenia 0 8 Biochemistry Parameters - Elevated Creatinine 0 8 6.9??????????Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST In the Phase 3 trials, the majority of Gleevec-treated patients experienced adverse reactions at some time. The most frequently reported adverse reactions were edema, fatigue, nausea, abdominal pain, diarrhea, rash, vomiting, myalgia, anemia, and anorexia. Drug was discontinued for adverse reactions in a total of 89 patients (5.4%). Superficial edema, most frequently periorbital or lower extremity edema was managed with diuretics, other supportive measures, or by reducing the dose of Gleevec [see Dosage and Administration (2. 12 )]. Severe (CTC Grade 3/4) edema was observed in 182 patients (11.1%). Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec are shown in Table 12. Overall the incidence of all grades of adverse reactions and the incidence of severe adverse reactions (CTC Grade 3 and above) were similar between the two treatment arms except for edema, which was reported more frequently in the 800 mg group. Table 12 Number (%) of Patients with Adverse Reactions Regardless of Relationship to Study Drug where Frequency is ???10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials Reported or Specified Term Imatinib 400 mg N=818 Imatinib 800 mg N=822 All Grades % Grades 3/4/5 % All Grades % Grades 3/4/5 % Edema 76.7 9.0 86.1 13.1 Fatigue/lethargy, malaise, asthenia 69.3 11.7 74.9 12.2 Nausea 58.1 9.0 64.5 7.8 Abdominal pain/cramping 57.2 13.8 55.2 11.8 Diarrhea 56.2 8.1 58.2 8.6 Rash/desquamation 38.1 7.6 49.8 8.9 Vomiting 37.4 9.2 40.6 7.5 Myalgia 32.2 5.6 30.2 3.8 Anemia 32.0 4.9 34.8 6.4 Anorexia 31.1 6.6 35.8 4.7 Other GI toxicity 25.2 8.1 28.1 6.6 Headache 22.0 5.7 19.7 3.6 Other pain (excluding tumor related pain) 20.4 5.9 20.8 5.0 Other dermatology/skin toxicity 17.6 5.9 20.1 5.7 Leukopenia 17.0 0.7 19.6 1.6 Other constitutional symptoms 16.7 6.4 15.2 4.4 Cough 16.1 4.5 14.5 3.2 Infection (without neutropenia) 15.5 6.6 16.5 5.6 Pruritus 15.4 5.4 18.9 4.3 Other neurological toxicity 15.0 6.4 15.2 4.9 Constipation 14.8 5.1 14.4 4.1 Other renal/genitourinary toxicity 14.2 6.5 13.6 5.2 Arthralgia (joint pain) 13.6 4.8 12.3 3.0 Dyspnea (shortness of breath) 13.6 6.8 14.2 5.6 Fever in absence of neutropenia (ANC3-6 x upper limit normal range [ULN], Grade 4 >6 x ULN), elevated bilirubin (Grade 3 >3-10 x ULN, Grade 4 >10 x ULN), elevated alkaline phosphatase, SGOT or SGPT (Grade 3 >5-20 x ULN, Grade 4 >20 x ULN), albumin (Grade 3 <20 g/L) 400 mg (n=73) 600 mg (n=74) % % CTC Grades 1 Grade 3 Grade 4 Grade 3 Grade 4 Hematology Parameters ??? Anemia 3 0 8 1 ??? Thrombocytopenia 0 0 1 0 ??? Neutropenia 7 3 8 3 Biochemistry Parameters ??? Elevated Creatinine 0 0 3 0 ??? Reduced Albumin 3 0 4 0 ??? Elevated Bilirubin 1 0 1 3 ??? Elevated Alkaline Phosphatase 0 0 3 0 ??? Elevated SGOT (AST) 4 0 3 3 ??? Elevated SGPT (ALT) 6 0 7 1 Adjuvant Treatment of GIST In Study 1, the majority of both Gleevec and placebo treated patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were similar to those reported in other clinical studies in other patient populations and include diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. No new adverse reactions were reported in the adjuvant GIST treatment setting that had not been previously reported in other patient populations including patients with unresectable and/or malignant metastatic GIST. Drug was discontinued for adverse reactions in 57 patients (17%) and 11 patients (3%) of the Gleevec and placebo treated patients respectively. Edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention and diarrhea), fatigue, low hemoglobin, and rash were the most frequently reported adverse reactions at the time of discontinuation. In Study 2, discontinuation of therapy due to adverse reactions occurred in 15 patients (8%) and 27 patients (14%) of the Gleevec 12-month and 36-month treatment arms, respectively.????As in previous trials the most common adverse reactions were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. Adverse reactions, regardless of relationship to study drug, that were reported in at least 5% of the patients treated with Gleevec are shown in Table 14 (Study 1) and Table 15 (Study 2).?? There were no deaths attributable to Gleevec treatment in either trial. Table 14: Adverse Reactions Regardless of Relationship to Study Drug Reported in Study 1 (???5% of Gleevec Treated Patients)(1) (1)All adverse reactions occurring in ???5% of patients are listed regardless of suspected relationship to treatment. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category. All CTC Grades CTC Grade 3 and above Gleevec (n=337) Placebo (n=345) Gleevec (n=337) Placebo (n=345) Preferred Term % % % % Diarrhea 59.3 29.3 3.0 1.4 Fatigue 57.0 40.9 2.1 1.2 Nausea 53.1 27.8 2.4 1.2 Periorbital Edema 47.2 14.5 1.2 0 Hemoglobin Decreased 46.9 27.0 0.6 0 Peripheral Edema 26.7 14.8 0.3 0 Rash (Exfoliative) 26.1 12.8 2.7 0 Vomiting 25.5 13.9 2.4 0.6 Abdominal Pain 21.1 22.3 3.0 1.4 Headache 19.3 20.3 0.6 0 Dyspepsia 17.2 13.0 0.9 0 Anorexia 16.9 8.7 0.3 0 Weight Increased 16.9 11.6 0.3 0 Liver enzymes (ALT) Increased 16.6 13.0 2.7 0 Muscle spasms 16.3 3.3 0 0 Neutrophil Count Decreased 16.0 6.1 3.3 0.9 Arthralgia 15.1 14.5 0 0.3 White Blood Cell Count Decreased 14.5 4.3 0.6 0.3 Constipation 12.8 17.7 0 0.3 Dizziness 12.5 10.7 0 0.3 Liver Enzymes (AST) Increased 12.2 7.5 2.1 0 Myalgia 12.2 11.6 0 0.3 Blood Creatinine Increased 11.6 5.8 0 0.3 Cough 11.0 11.3 0 0 Pruritus 11.0 7.8 0.9 0 Weight Decreased 10.1 5.2 0 0 Hyperglycemia 9.8 11.3 0.6 1.7 Insomnia 9.8 7.2 0.9 0 Lacrimation Increased 9.8 3.8 0 0 Alopecia 9.5 6.7 0 0 Flatulence 8.9 9.6 0 0 Rash 8.9 5.2 0.9 0 Abdominal Distension 7.4 6.4 0.3 0.3 Back Pain 7.4 8.1 0.6 0 Pain in Extremity 7.4 7.2 0.3 0 Hypokalemia 7.1 2.0 0.9 0.6 Depression 6.8 6.4 0.9 0.6 Facial Edema 6.8 1.2 0.3 0 Blood Alkaline Phosphatase Increased 6.5 7.5 0 0 Dry skin 6.5 5.2 0 0 Dysgeusia 6.5 2.9 0 0 Abdominal Pain Upper 6.2 6.4 0.3 0 Neuropathy Peripheral 5.9 6.4 0 0 Hypocalcemia 5.6 1.7 0.3 0 Leukopenia 5.0 2.6 0.3 0 Platelet Count Decreased 5.0 3.5 0 0 Stomatitis 5.0 1.7 0.6 0 Upper Respiratory Tract Infection 5.0 3.5 0 0 Vision Blurred 5.0 2.3 0 0 Table 15: Adverse Reactions Regardless of Relationship to Study Drug by Preferred Term All Grades and 3/4 Grades (???5% of Gleevec Treated Patients) Study 2(1) (1)All adverse reactions occurring in ???5% of patients are listed regardless of suspected relationship to treatment. A patient with multiple occurrences of an adverse reaction is counted only once in the adverse reaction category. Preferred Term All CTC Grades CTC Grades 3 and above Gleevec 12 Months (N=194) % Gleevec 36 Months (N=198) % Gleevec 12 Months (N=194) % Gleevec 36 Months (N=198) % Patients with at least one AE 99.0 100.0 20.1 32.8 Hemoglobin decreased 72.2 80.3 0.5 0.5 Periorbital edema 59.3 74.2 0.5 1.0 Blood lactate dehydrogenase increased 43.3 60.1 0 0 Diarrhea 43.8 54.0 0.5 2.0 Nausea 44.8 51.0 1.5 0.5 Muscle spasms 30.9 49.0 0.5 1.0 Fatigue 48.5 48.5 1.0 0.5 White blood cell count decreased 34.5 47.0 2.1 3.0 Pain 25.8 45.5 1.0 3.0 Blood creatinine increased 30.4 44.4 0 0 Edema peripheral 33.0 40.9 0.5 1.0 Dermatitis 29.4 38.9 2.1 1.5 Aspartate aminotransferase increased 30.9 37.9 1.5 3.0 Alanine aminotransferase increased 28.9 34.3 2.1 3.0 Neutrophil count decreased 24.2 33.3 4.6 5.1 Hypoproteinemia 23.7 31.8 0 0 Infection 13.9 27.8 1.5 2.5 Weight increased 13.4 26.8 0 0.5 Pruritus 12.9 25.8 0 0 Flatulence 19.1 24.7 1.0 0.5 Vomiting 10.8 22.2 0.5 1.0 Dyspepsia 17.5 21.7 0.5 1.0 Hypoalbuminemia 11.9 21.2 0 0 Edema 10.8 19.7 0 0.5 Abdominal distension 11.9 19.2 0.5 0 Headache 8.2 18.2 0 0 Lacrimation increased 18.0 17.7 0 0 Arthralgia 8.8 17.2 0 1.0 Blood alkaline phosphatase increased 10.8 16.7 0 0.5 Dyspnea 6.2 16.2 0.5 1.5 Myalgia 9.3 15.2 0 1.0 Platelet count decreased 11.3 14.1 0 0 Blood bilirubin increased 11.3 13.1 0 0 Dysgeusia 9.3 12.6 0 0 Paresthesia 5.2 12.1 0 0.5 Vision blurred 10.8 11.1 1.0 0.5 Alopecia 11.3 10.6 0 0 Decreased appetite 9.8 10.1 0 0 Constipation 8.8 9.6 0 0 Pyrexia 6.2 9.6 0 0 Depression 3.1 8.1 0 0 Abdominal pain 2.6 7.6 0 0 Conjunctivitis 5.2 7.6 0 0 Photosensitivity reaction 3.6 7.1 0 0 Dizziness 4.6 6.6 0.5 0 Hemorrhage 3.1 6.6 0 0 Dry skin 6.7 6.1 0.5 0 Nasopharyngitis 1.0 6.1 0 0.5 Palpitations 5.2 5.1 0 0 6.10??????????Additional Data from Multiple Clinical Trials The following adverse reactions have been reported during clinical trials of Gleevec. Cardiac Disorders: Estimated 1%???10%: palpitations, pericardial effusion Estimated 0.1%-1%: congestive cardiac failure, tachycardia, pulmonary edema Estimated 0.01%-0.1%: arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris Vascular Disorders:?? Estimated 1%-10%: flushing, hemorrhage Estimated 0.1%-1%: hypertension, hypotension, peripheral coldness, Raynauds phenomenon, hematoma, subdural hematoma Investigations: Estimated 1%-10%: blood CPK increased, blood amylase increased Estimated 0.1%???1%: blood LDH increased Skin and Subcutaneous Tissue Disorders: Estimated 1%???10%: dry skin, alopecia, face edema, erythema, photosensitivity reaction, nail disorder, purpura Estimated 0.1%???1%: exfoliative dermatitis, bullous eruption, psoriasis, rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased tendency to bruise, hypotrichosis, skin hypopigmentation, skin hyperpigmentation, onychoclasis, folliculitis, petechiae, erythema multiforme Estimated 0.01%???0.1%: vesicular rash, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, acute febrile neutrophilic dermatosis (Sweet???s syndrome), nail discoloration, angioneurotic edema, leucocytoclastic vasculitis Gastrointestinal Disorders:?? Estimated 1%-10%: abdominal distention, gastroesophageal reflux, dry mouth, gastritis Estimated 0.1%-1%: gastric ulcer, stomatitis, mouth ulceration, eructation, melena, esophagitis, ascites, hematemesis, chelitis, dysphagia, pancreatitis Estimated 0.01%-0.1%: colitis, ileus, inflammatory bowel disease General Disorders and Administration Site Conditions: Estimated 1%-10%: weakness, anasarca, chills Estimated 0.1%-1%: malaise Blood and Lymphatic System Disorders: Estimated 1%-10%: pancytopenia, febrile neutropenia, lymphopenia, eosinophila Estimated 0.1%-1%: thrombocythemia, bone marrow depression, lymphadenopathy Estimated 0.01%-0.1%: hemolytic anemia, aplastic anemia Hepatobiliary Disorders: Estimated 0.1%-1%: hepatitis, jaundice Estimated 0.01%-0.1%: hepatic failure and hepatic necrosis1?? Immune System Disorders: Estimated 0.01%-0.1%: angioedema Infections and Infestations: Estimated 0.1%-1%: sepsis, herpes simplex, herpes zoster, cellulitis, urinary tract infection, gastroenteritis Estimated 0.01%-0.1%: fungal infection Metabolism and Nutrition Disorders: ?? Estimated 1%-10%: weight decreased, decreased appetite Estimated 0.1%???1%: dehydration, gout, increased appetite, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia, hyperkalemia, hypomagnesemia Musculoskeletal and Connective Tissue Disorders: Estimated 1%-10%: joint swelling Estimated 0.1%???1%: joint and muscle stiffness, muscular weakness, arthritis Nervous System/Psychiatric Disorders: Estimated 1%-10%: paresthesia, hypesthesia Estimated 0.1%-1%: syncope, peripheral neuropathy, somnolence, migraine, memory impairment, libido decreased, sciatica, restless leg syndrome, tremor Estimated 0.01%-0.1%: increased intracranial pressure1, confusional state, convulsions, optic neuritis Renal and Urinary Disorders: Estimated 0.1%-1%: renal failure acute, urinary frequency increased, hematuria, renal pain Reproductive System and Breast Disorders: Estimated 0.1%-1%: breast enlargement, menorrhagia, sexual dysfunction, gynecomastia, erectile dysfunction, menstruation irregular, nipple pain, scrotal edema Respiratory, Thoracic and Mediastinal Disorders: Estimated 1%-10%: epistaxis Estimated 0.1%-1%: pleural effusion Estimated 0.01%-0.1%: interstitial pneumonitis, pulmonary fibrosis, pleuritic pain, pulmonary hypertension, pulmonary hemorrhage Eye, Ear and Labyrinth Disorders: Estimated 1%???10%: conjunctivitis, vision blurred, orbital edema, conjunctival hemorrhage, dry eye Estimated 0.1%???1%: vertigo, tinnitus, eye irritation, eye pain, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, hearing loss, cataract Estimated 0.01%-0.1%: papilledema1, glaucoma 1Including some fatalities 6.11??????????Postmarketing Experience The following additional adverse reactions have been identified during post approval use of Gleevec. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous System Disorders: cerebral edema1?? Eye Disorders: vitreous hemorrhage Cardiac Disorders: pericarditis, cardiac tamponade1 Vascular Disorders: thrombosis/embolism, anaphylactic shock Respiratory, Thoracic and Mediastinal Disorders: acute respiratory failure1, interstitial lung disease Gastrointestinal Disorders: ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation1??[see Warnings and Precautions (5.6)],??diverticulitis, gastric antral vascular ectasia Skin and Subcutaneous Tissue Disorders: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS) Musculoskeletal and Connective Tissue Disorders: avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children Reproduction Disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst 1Including some fatalities
INDICATIONS & USAGE SECTION.
1??????????INDICATIONS AND USAGE Gleevec is a kinase inhibitor indicated for the treatment of: Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (1.1) Patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) after failure of interferon-alpha therapy (1.2) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) (1.3) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy (1.4) Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements (1.5) Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown (1.6) Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFR?? fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFR?? fusion kinase negative or unknown (1.7) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP) (1.8)?? Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST) (1.9) Adjuvant treatment of adult patients following resection of Kit (CD117) positive GIST (1.10) 1.1??????????Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML) Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia in chronic phase. 1.2??????????Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After Interferon-alpha (IFN) Therapy Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. 1.3??????????Adult patients with Ph+ Acute Lymphoblastic Leukemia (ALL) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia. 1.4??????????Pediatric patients with Ph+ Acute Lymphoblastic Leukemia (ALL) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. 1.5??????????Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR (platelet-derived growth factor receptor) gene re-arrangements. 1.6??????????Aggressive Systemic Mastocytosis (ASM) Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown. 1.7??????????Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL) Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFR?? fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFR?? fusion kinase negative or unknown. 1.8??????????Dermatofibrosarcoma Protuberans (DFSP) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. 1.9??????????Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors. 1.10??????????Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.
DOSAGE & ADMINISTRATION SECTION.
2??????????DOSAGE AND ADMINISTRATION Therapy should be initiated by a physician experienced in the treatment of patients with hematological malignancies or malignant sarcomas, as appropriate. The prescribed dose should be administered orally, with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once-daily, whereas a dose of 800??mg should be administered as 400 mg twice a day. In children, Gleevec treatment can be given as a once-daily dose in CML and Ph+ ALL. Alternatively, in children with CML the daily dose may be split into two-one portion dosed in the morning and one portion in the evening. There is no experience with Gleevec treatment in children under 1 year of age. For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice. The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100 mg tablet, and 200 mL for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete disintegration of the tablet(s). For daily dosing of 800 mg and above, dosing should be accomplished using the 400 mg tablet to reduce exposure to iron. Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity. Adults with Ph+ CML CP (2.1): ?????????? 400 mg/day Adults with Ph+ CML AP or BC (2.1): ?????????? 600 mg/day Pediatrics with Ph+ CML CP (2.2): ?????????? 340 mg/m2/day Adults with Ph+ ALL (2.3): ?????????? 600 mg/day Pediatrics with Ph+ ALL (2.4): ?????????? 340 mg/m2/day Adults with MDS/MPD (2.5): ?????????? 400 mg/day Adults with ASM (2.6): ?????????? 100 mg/day or 400 mg/day Adults with HES/CEL (2.7): ?????????? 100 mg/day or 400 mg/day Adults with DFSP (2.8): ?????????? 800 mg/day Adults with metastatic and/or unresectable GIST (2.9): ?????????? 400 mg/day Adjuvant treatment of adults with GIST (2.10): ?????????? 400 mg/day Patients with mild to moderate hepatic impairment (2.11): ?????????? 400 mg/day Patients with severe hepatic impairment (2.11): ?????????? 300 mg/day All doses of Gleevec should be taken with a meal and a large glass of water. Doses of 400 mg or 600 mg should be administered once-daily, whereas a dose of 800 mg should be administered as 400 mg twice a day. Gleevec can be dissolved in water or apple juice for patients having difficulty swallowing. Daily dosing of 800 mg and above should be accomplished using the 400 mg tablet to reduce exposure to iron. 2.1??????????Adult Patients with Ph+ CML CP, AP, and BC The recommended dose of Gleevec is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult patients in accelerated phase or blast crisis. In CML, a dose increase from 400 mg to 600 mg in adult patients with chronic phase disease, or from 600 mg to 800 mg (given as 400 mg twice-daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6-12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response. 2.2??????????Pediatric Patients with Ph+ CML CP The recommended dose of Gleevec for children with newly diagnosed Ph+ CML is 340 mg/m2/day (not to exceed 600 mg). 2.3??????????Adults Patients with Ph+ ALL The recommended dose of Gleevec is 600 mg/day for adult patients with relapsed/refractory Ph+ ALL. 2.4??????????Pediatric Patients with Ph+ ALL The recommended dose of Gleevec to be given in combination with chemotherapy to children with newly diagnosed Ph+ ALL is 340 mg/m2/day (not to exceed 600 mg). 2.5??????????MDS/MPD The recommended dose of Gleevec is 400 mg/day for adult patients with MDS/MPD. 2.6??????????ASM The recommended dose of Gleevec is 400 mg/day for adult patients with ASM without the D816V c-Kit mutation. If c-Kit mutational status is not known or unavailable, treatment with Gleevec 400??mg/day may be considered for patients with ASM not responding satisfactorily to other therapies. For patients with ASM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFR??, a starting dose of 100 mg/day is recommended. Dose increase from 100 mg to 400 mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. 2.7??????????HES/CEL The recommended dose of Gleevec is 400 mg/day for adult patients with HES/CEL. For HES/CEL patients with demonstrated FIP1L1-PDGFR?? fusion kinase, a starting dose of 100??mg/day is recommended. Dose increase from 100??mg to 400??mg for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy.?? 2.8??????????DFSP The recommended dose of Gleevec is 800 mg/day for adult patients with DFSP. 2.9??????????Metastatic or Unresectable GIST The recommended dose of Gleevec is 400 mg/day for adult patients with unresectable and/or metastatic, malignant GIST. A dose increase up to 800 mg daily (given as 400 mg twice-daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions. 2.10??????????Adjuvant GIST The recommended dose of Gleevec is 400 mg/day for the adjuvant treatment of adult patients following complete gross resection of GIST. In clinical trials, one year of Gleevec and three years of Gleevec were studied. In the patient population defined in Study 2,??three years of Gleevec is recommended??[see Clinical Studies (14.8)]. The optimal treatment duration with Gleevec is not known. 2.11??????????Dose Modification Guidelines Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital). If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dosage of Gleevec should be increased by at least 50%, and clinical response should be carefully monitored [see Drug Interactions (7.1)]. Hepatic Impairment: Patients with mild and moderate hepatic impairment do not require a dose adjustment and should be treated per the recommended dose. A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment [see Use in Specific Populations (8.6)]. Renal Impairment: Patients with moderate renal impairment (CrCL=20-39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated. Doses greater than 600 mg are not recommended in patients with mild renal impairment (CrCL=40-59 mL/min). For patients with moderate renal impairment doses greater than 400 mg are not recommended. Imatinib should be used with caution in patients with severe renal impairment. A dose of 100 mg/day was tolerated in two patients with severe renal impairment [see Warnings and Precautions (5.3), Use in Specific Populations (8.7)]. 2.12??????????Dose Adjustment for Hepatotoxicity and Non-Hematologic Adverse Reactions If elevations in bilirubin greater than 3 times the institutional upper limit of normal (IULN) or in liver transaminases greater than 5 times the IULN occur, Gleevec should be withheld until bilirubin levels have returned to a less than 1.5 times the IULN and transaminase levels to less than 2.5 times the IULN. In adults, treatment with Gleevec may then be continued at a reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg or 800 mg to 600 mg). In children, daily doses can be reduced under the same circumstances from 340 mg/m2/day to 260 mg/m2/day. If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), Gleevec should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event. 2.13??????????Dose Adjustment for Hematologic Adverse Reactions Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1. Table 1 Dose Adjustments for Neutropenia and Thrombocytopenia ASM associated with eosinophilia (starting dose 100 mg) ANC <1.0 x 109/L and/or platelets <50 x 109/L Stop Gleevec until ANC ???1.5 x 109/L and platelets ???75 x 109/L Resume treatment with Gleevec at previous dose (i.e., dose before severe adverse reaction) HES/CEL with FIP1L1-PDGFR?? fusion kinase (starting dose 100??mg) ANC <1.0 x 109/L and/or platelets <50 x 109/L Stop Gleevec until ANC ???1.5 x 109/L and platelets ???75 x 109/L Resume treatment with Gleevec at previous dose (i.e., dose before severe adverse reaction) Chronic Phase CML (starting dose 400 mg) MDS/MPD, ASM and HES/CEL (starting dose 400 mg) GIST (starting dose 400 mg) ANC <1.0 x 109/L and/or platelets <50 x 109/L Stop Gleevec until ANC ???1.5 x 109/L and platelets ???75 x 109/L Resume treatment with Gleevec at the original starting dose of 400 mg If recurrence of ANC <1.0 x 109/L and/or platelets <50 x 109/L, repeat step 1 and resume Gleevec at a reduced dose of 300 mg Ph+ CML : Accelerated Phase and Blast Crisis (starting dose 600 mg) Ph+ ALL (starting dose 600 mg) ANC <0.5 x 109/L and/or platelets <10 x 109/L Check if cytopenia is related to leukemia (marrow aspirate or biopsy) If cytopenia is unrelated to leukemia, reduce dose of Gleevec to 400 mg If cytopenia persists 2 weeks, reduce further to 300 mg If cytopenia persists 4 weeks and is still unrelated to leukemia, stop Gleevec until ANC ???1 x 109/L and platelets ???20 x 109/L and then resume treatment at 300 mg DFSP (starting dose 800 mg) ANC <1.0 x 109/L and/or platelets <50 x 109/L Stop Gleevec until ANC ???1.5 x 109/L and platelets ???75 x 109/L Resume treatment with Gleevec at 600 mg In the event of recurrence of ANC <1.0 x 109/L and/or platelets <50 x 109/L, repeat step 1 and resume Gleevec at reduced dose of 400 mg Pediatric newly diagnosed chronic phase CML (starting dose 340 mg/m2) ANC <1.0 x 109/L and/or platelets <50 x 109/L Stop Gleevec until ANC ???1.5 x 109/L and platelets ???75 x 109/L Resume treatment with Gleevec at previous dose (i.e., dose before severe adverse reaction) In the event of recurrence of ANC <1.0 x 109/L and/or platelets <50 x 109/L, repeat step 1 and resume Gleevec at reduced dose of 260 mg/m2
HOW SUPPLIED SECTION.
16??????????HOW SUPPLIED/STORAGE AND HANDLING Each film-coated tablet contains 100 mg or 400 mg of imatinib free base. 100 mg Tablets Very dark yellow to brownish orange, film-coated tablets, round, biconvex with bevelled edges, debossed with ???NVR??? on one side, and ???SA??? with score on the other side. Bottles of 90 tablets NDC 0078-0401-34 NDC 69189-0403-1 Single dose pack with 1 tablet as repackaged by Avera McKennan Hospital
11??????????DESCRIPTION Imatinib is a small molecule kinase inhibitor. Gleevec film-coated tablets contain imatinib mesylate equivalent to 100??mg or 400 mg of imatinib free base. Imatinib mesylate is designated chemically as 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate and its structural formula is: Imatinib mesylate is a white to off-white to brownish or yellowish tinged crystalline powder. Its molecular formula is C29H31N7O ??? CH4SO3 and its molecular weight is 589.7. Imatinib mesylate is soluble in aqueous buffers ???pH 5.5 but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers. In non-aqueous solvents, the drug substance is freely soluble to very slightly soluble in dimethyl sulfoxide, methanol, and ethanol, but is insoluble in n-octanol, acetone, and acetonitrile. Inactive Ingredients: colloidal silicon dioxide (NF); crospovidone (NF); hydroxypropyl methylcellulose (USP); magnesium stearate (NF); and microcrystalline cellulose (NF). Tablet coating: ferric oxide, red (NF); ferric oxide, yellow (NF); hydroxypropyl methylcellulose (USP); polyethylene glycol (NF) and talc (USP).
INFORMATION FOR PATIENTS SECTION.
17??????????PATIENT COUNSELING INFORMATION Dosing and Administration Advise patients to take Gleevec exactly as prescribed, not to change their dose or to stop taking Gleevec unless they are told to do so by their doctor. If the patient missed a dose of Gleevec, the patient should take the next scheduled dose at its regular time. The patient should not take two doses at the same time. Advise patients to take Gleevec with a meal and a large glass of water. Pregnancy and Breastfeeding Advise patients to inform their doctor if they are or think they may be pregnant. Advise women of reproductive potential to avoid becoming pregnant while taking Gleevec. Sexually active female patients taking Gleevec should use highly effective contraception. Avoid breastfeeding while taking Gleevec. Adverse Reactions Advise patients to tell their doctor if they experience side effects during Gleevec therapy including fever, shortness of breath, blood in their stools, jaundice, sudden weight gain, symptoms of cardiac failure, or if they have a history of cardiac disease or risk factors for cardiac failure. Drug Interactions Gleevec and certain other medicines such as warfarin, erythromycin, and phenytoin, including over-the-counter medications such as herbal products, can interact with each other. Advise patients to tell their doctor if they are taking or plan to take iron supplements. Avoid grapefruit juice and other foods known to inhibit CYP3A4 while taking Gleevec. Pediatric Advise patients that growth retardation has been reported in children and pre-adolescents receiving Gleevec. The long term effects of prolonged treatment with Gleevec on growth in children are unknown. Therefore, close monitoring of growth in children under Gleevec treatment is recommended. Driving and Using Machines Advise patients that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with Gleevec. Therefore, caution patients about driving a car or operating machinery. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ?? Novartis T2015-25 January 2015
CLINICAL STUDIES SECTION.
14??????????CLINICAL STUDIES 14.1??????????Chronic Myeloid Leukemia Chronic Phase, Newly Diagnosed: An open-label, multicenter, international randomized Phase 3 study (Gleevec versus INF+Ara-C) has been conducted in patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. This study compared treatment with either single-agent Gleevec or a combination of interferon-alpha (IFN) plus cytarabine (Ara-C). Patients were allowed to cross over to the alternative treatment arm if they failed to show a complete hematologic response (CHR) at 6 months, a major cytogenetic response (MCyR) at 12 months, or if they lost a CHR or MCyR. Patients with increasing WBC or severe intolerance to treatment were also allowed to cross over to the alternative treatment arm with the permission of the study monitoring committee (SMC). In the Gleevec arm, patients were treated initially with 400 mg daily. Dose escalations were allowed from 400 mg daily to 600 mg daily, then from 600 mg daily to 800 mg daily. In the IFN arm, patients were treated with a target dose of IFN of 5 MIU/m2/day subcutaneously in combination with subcutaneous Ara-C 20 mg/m2/day for 10 days/month. A total of 1,106 patients were randomized from 177 centers in 16 countries, 553 to each arm. Baseline characteristics were well balanced between the two arms. Median age was 51 years (range 18-70 years), with 21.9% of patients ???60 years of age. There were 59% males and 41% females; 89.9% Caucasian and 4.7% black patients. At the cut-off for this analysis (7 years after last patient had been recruited), the median duration of first-line treatment was 82 and 8??months in the Gleevec and IFN arm, respectively. The median duration of second-line treatment with Gleevec was 64 months. Sixty percent of patients randomized to Gleevec are still receiving first-line treatment. In these patients, the average dose of Gleevec was 403 mg ?? 57 mg. Overall, in patients receiving first line Gleevec, the average daily dose delivered was 406 mg ?? 76 mg. Due to discontinuations and cross-overs, only 2% of patients randomized to IFN were still on first-line treatment. In the IFN arm, withdrawal of consent (14%) was the most frequent reason for discontinuation of first-line therapy, and the most frequent reason for cross over to the Gleevec arm was severe intolerance to treatment (26%) and progression (14%). The primary efficacy endpoint of the study was progression-free survival (PFS). Progression was defined as any of the following events: progression to accelerated phase or blast crisis (AP/BC), death, loss of CHR or MCyR, or in patients not achieving a CHR an increasing WBC despite appropriate therapeutic management. The protocol specified that the progression analysis would compare the intent to treat (ITT) population: patients randomized to receive Gleevec were compared with patients randomized to receive IFN. Patients that crossed over prior to progression were not censored at the time of cross-over, and events that occurred in these patients following cross-over were attributed to the original randomized treatment. The estimated rate of progression-free survival at 84 months in the ITT population was 81.2 % [95% CI: 78, 85] in the Gleevec arm and 60.6 % [56, 65] in the IFN arm (p18 years old. Patients were treated at doses of 260 mg/m2/day (n=3), 340 mg/m2/day (n=4), 440??mg/m2/day (n=5) and 570 mg/m2/day (n=2). In the 13 patients for whom cytogenetic data are available, 4 achieved a major cytogenetic response, 7 achieved a complete cytogenetic response, and 2 had a minimal cytogenetic response. In a second study, 2 of 3 patients with Ph+ chronic phase CML resistant to interferon-alpha therapy achieved a complete cytogenetic response at doses of 242 and 257 mg/m2/day. 14.3??????????Acute Lymphoblastic Leukemia A total of 48 Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) patients with relapsed/refractory disease were studied, 43 of whom received the recommended Gleevec dose of 600 mg/day. In addition 2 patients with relapsed/refractory Ph+ ALL received Gleevec 600 mg/day in a phase 1 study. Confirmed and unconfirmed hematologic and cytogenetic response rates for the 43 relapsed/refractory Ph+ALL phase 2 study patients and for the 2 phase 1 patients are shown in Table 21. The median duration of hematologic response was 3.4 months and the median duration of MCyR was 2.3 months. Table 21 Effect of Gleevec on Relapsed/Refractory Ph+ ALL ?? Phase 2 Study (N=43) n(%) Phase 1 Study (N=2) n(%) CHR 8 (19) 2 (100) NEL 5 (12) RTC/PHR 11 (26) MCyR 15 (35) CCyR 9 (21) PCyR 6 (14) 14.4??????????Pediatric ALL Pediatric and young adult patients with very high risk ALL, defined as those with an expected 5-year event-free survival (EFS) less than 45%, were enrolled after induction therapy on a multicenter, non-randomized cooperative group pilot protocol. The safety and effectiveness of Gleevec (340 mg/m2/day) in combination with intensive chemotherapy was evaluated in a subgroup of patients with Ph+ ALL. The protocol included intensive chemotherapy and hematopoietic stem cell transplant after 2 courses of chemotherapy for patients with an appropriate HLA-matched family donor. There were 92 eligible patients with Ph+ ALL enrolled. The median age was 9.5 years (1 to 21 years), 64% were male, 75% were white, 9% were Asian/Pacific Islander, and 5% were black. In 5 successive cohorts of patients, Gleevec exposure was systematically increased by earlier introduction and prolonged duration. Cohort 1 received the lowest intensity and cohort 5 received the highest intensity of Gleevec exposure. There were 50 patients with Ph+ ALL assigned to cohort 5 all of whom received Gleevec plus chemotherapy; 30 were treated exclusively with chemotherapy and Gleevec and 20 received chemotherapy plus Gleevec and then underwent hematopoietic stem cell transplant, followed by further Gleevec treatment. Patients in cohort 5 treated with chemotherapy received continuous daily exposure to Gleevec beginning in the first course of post induction chemotherapy continuing through maintenance cycles 1 through 4 chemotherapy. During maintenance cycles 5 through 12 Gleevec was administered 28 days out of the 56 day cycle. Patients who underwent hematopoietic stem cell transplant received 42 days of Gleevec prior to HSCT, and 28 weeks (196 days) of Gleevec after the immediate post transplant period. The estimated 4-year EFS of patients in cohort 5 was 70% (95% CI: 54, 81). The median follow-up time for EFS at data cutoff in cohort 5 was 40.5 months. 14.5??????????Myelodysplastic/Myeloproliferative Diseases An open-label, multicenter, phase 2 clinical trial was conducted testing Gleevec in diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 7 patients with MDS/MPD. These patients were treated with Gleevec 400 mg daily. The ages of the enrolled patients ranged from 20 to 86 years. A further 24 patients with MDS/MPD aged 2 to 79 years were reported in 12 published case reports and a clinical study. These patients also received Gleevec at a dose of 400 mg daily with the exception of three patients who received lower doses. Of the total population of 31 patients treated for MDS/MPD, 14 (45%) achieved a complete hematological response and 12 (39%) a major cytogenetic response (including 10 with a complete cytogenetic response). Sixteen patients had a translocation, involving chromosome 5q33 or 4q12, resulting in a PDGFR gene re-arrangement. All of these patients responded hematologically (13 completely). Cytogenetic response was evaluated in 12 out of 14 patients, all of whom responded (10 patients completely). Only 1 (7%) out of the 14 patients without a translocation associated with PDGFR gene re-arrangement achieved a complete hematological response and none achieved a major cytogenetic response. A further patient with a PDGFR gene re-arrangement in molecular relapse after bone marrow transplant responded molecularly. Median duration of therapy was 12.9 months (0.8-26.7) in the 7 patients treated within the phase 2 study and ranged between 1 week and more than 18 months in responding patients in the published literature. Results are provided in Table 22. Response durations of phase 2 study patients ranged from 141+ days to 457+ days. Table 22 Response in MDS/MPD 1 NE: Not Evaluable Number of patients Complete Hematologic Response Major Cytogenetic Response N n (%) n (%) Overall Population 31 14 (45) 12 (39) Chromosome 5 Translocation 14 11 (79) 11 (79) Chromosome 4 Translocation 2 2 (100) 1 (50) Others / no Translocation 14 1 (7) 0 Molecular Relapse 1 NE1 NE1 14.6??????????Aggressive Systemic Mastocytosis One open-label, multicenter, phase 2 study was conducted testing Gleevec in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 5??patients with aggressive systemic mastocytosis (ASM) treated with 100 mg to 400 mg of Gleevec daily. These 5 patients ranged from 49 to 74??years of age. In addition to these 5 patients, 10 published case reports and case series describe the use of Gleevec in 23??additional patients with ASM aged 26 to 85??years who also received 100 mg to 400 mg of Gleevec daily. Cytogenetic abnormalities were evaluated in 20 of the 28??ASM patients treated with Gleevec from the published reports and in the phase 2 study. Seven of these 20??patients had the FIP1L1-PDGFR?? fusion kinase (or CHIC2 deletion). Patients with this cytogenetic abnormality were predominantly males and had eosinophilia associated with their systemic mast cell disease. Two patients had a Kit mutation in the juxtamembrane region (one Phe522Cys and one K509I) and four patients had a D816V c-Kit mutation (not considered sensitive to Gleevec), one with concomitant CML. Of the 28??patients treated for ASM, 8 (29%) achieved a complete hematologic response and 9 (32%) a partial hematologic response (61% overall response rate). Median duration of Gleevec therapy for the 5 ASM patients in the phase 2 study was 13??months (range 1.4-22.3??months) and between 1??month and more than 30??months in the responding patients described in the published medical literature. A summary of the response rates to Gleevec in ASM is provided in Table??23. Response durations of literature patients ranged from 1+ to 30+ months. Table 23 Response in ASM * Patient had concomitant CML and ASM Cytogenetic Abnormality Number of Patients N Complete Hematologic Response N (%) Partial Hematologic Response N (%) FIP1L1-PDGFR?? Fusion Kinase (or CHIC2 Deletion) 7 7(100) 0 Juxtamembrane Mutation 2 0 2 (100) Unknown or No Cytogenetic Abnormality Detected 15 0 7 (44) D816V Mutation 4 1* (25) 0 Total 28 8 (29) 9 (32) Gleevec has not been shown to be effective in patients with less aggressive forms of systemic mastocytosis (SM). Gleevec is therefore not recommended for use in patients with cutaneous mastocytosis, indolent systemic mastocytosis (smoldering SM or isolated bone marrow mastocytosis), SM with an associated clonal hematological non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma or extracutaneous mastocytoma. Patients that harbor the D816V mutation of c-Kit are not sensitive to Gleevec and should not receive Gleevec. 14.7??????????Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia One open-label, multicenter, phase 2 study was conducted testing Gleevec in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 14??patients with Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia (HES/CEL). HES patients were treated with 100??mg to 1000??mg of Gleevec daily. The ages of these patients ranged from 16 to 64??years. A further 162??patients with HES/CEL aged 11 to 78??years were reported in 35??published case reports and case series. These patients received Gleevec at doses of 75??mg to 800??mg daily. Hematologic response rates are summarized in Table 24. Response durations for literature patients ranged from 6+ weeks to 44 months. Table 24 Response in HES/CEL Cytogenetic Abnormality Number of Patients Complete Hematological Response N (%) Partial Hematological Response N (%) Positive FIP1L1-PDGFR?? Fusion Kinase 61 61 (100) 0 Negative FIP1L1-PDGFR?? Fusion Kinase 56 12 (21) 9 (16) Unknown Cytogenetic Abnormality 59 34 (58) 7 (12) Total 176 107 (61) 23 (13) 14.8??????????Dermatofibrosarcoma Protuberans Dermatofibrosarcoma Protuberans (DFSP) is a cutaneous soft tissue sarcoma. It is characterized by a translocation of chromosomes 17 and 22 that results in the fusion of the collagen type 1 alpha 1 gene and the PDGF B gene. An open-label, multicenter, phase 2 study was conducted testing Gleevec in a diverse population of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 12 patients with DFSP who were treated with Gleevec 800 mg daily (age range 23 to 75 years). DFSP was metastatic, locally recurrent following initial surgical resection and not considered amenable to further surgery at the time of study entry. A further 6 DFSP patients treated with Gleevec are reported in 5 published case reports, their ages ranging from 18 months to 49 years. The total population treated for DFSP therefore comprises 18 patients, 8 of them with metastatic disease. The adult patients reported in the published literature were treated with either 400 mg (4 cases) or 800 mg (1 case) Gleevec daily. A single pediatric patient received 400 mg/m2/daily, subsequently increased to 520 mg/m2/daily. Ten patients had the PDGF B gene rearrangement, 5 had no available cytogenetics and 3 had complex cytogenetic abnormalities. Responses to treatment are described in Table 25. Table 25 Response in DFSP * 5 patients made disease free by surgery Number of Patients (n=18) % Complete Response 7 39 Partial Response * 8 44 Total Responders 15 83 Twelve of these 18 patients either achieved a complete response (7 patients) or were made disease free by surgery after a partial response (5 patients, including one child) for a total complete response rate of 67%. A further 3 patients achieved a partial response, for an overall response rate of 83%. Of the 8 patients with metastatic disease, five responded (62%), three of them completely (37%). For the 10 study patients with the PDGF B gene rearrangement there were 4 complete and 6 partial responses. The median duration of response in the phase 2 study was 6.2 months, with a maximum duration of 24.3 months, while in the published literature it ranged between 4 weeks and more than 20 months. 14.9??????????Gastrointestinal Stromal Tumors Unresectable and/or Malignant Metastatic GIST Two open-label, randomized, multinational Phase 3 studies were conducted in patients with unresectable or metastatic malignant gastrointestinal stromal tumors (GIST). The two study designs were similar allowing a predefined combined analysis of safety and efficacy. A total of 1640 patients were enrolled into the two studies and randomized 1:1 to receive either 400 mg or 800 mg orally daily continuously until disease progression or unacceptable toxicity. Patients in the 400 mg daily treatment group who experienced disease progression were permitted to crossover to receive treatment with 800 mg daily. The studies were designed to compare response rates, progression-free survival and overall survival between the dose groups. Median age at patient entry was 60 years. Males comprised 58% of the patients enrolled. All patients had a pathologic diagnosis of CD117 positive unresectable and/or metastatic malignant GIST. The primary objective of the two studies was to evaluate either progression-free survival (PFS) with a secondary objective of overall survival (OS) in one study or overall survival with a secondary objective of PFS in the other study. A planned analysis of both OS and PFS from the combined datasets from these two studies was conducted. Results from this combined analysis are shown in Table 26. Table 26 Overall Survival, Progression-Free Survival and Tumor Response Rates in the Phase 3 GIST Trials Gleevec 400 mg N=818 Gleevec 800 mg N=822 Progression-Free Survival (months) ??????????Median 18.9 23.2 ??????????95% CI 17.4-21.2 20.8-24.9 Overall Survival (months) 49.0 48.7 ??????????95% CI 45.3-60.0 45.3-51.6 Best Overall Tumor Response ??????????Complete Response (CR) 43 (5.3%) 41 (5.0%) ??????????Partial Response (PR) 377 (46.1%) 402 (48.9%) Median follow up for the combined studies was 37.5 months. There were no observed differences in overall survival between the treatment groups (p=0.98). Patients who crossed over following disease progression from the 400 mg/day treatment group to the 800 mg/day treatment group (n=347) had a 3.4 month median and a 7.7 month mean exposure to Gleevec following crossover. One open-label, multinational Phase 2 study was conducted in patients with Kit (CD117) positive unresectable or metastatic malignant GIST. In this study, 147 patients were enrolled and randomized to receive either 400 mg or 600 mg orally q.d. for up to 36 months. The primary outcome of the study was objective response rate. Tumors were required to be measurable at entry in at least one site of disease, and response characterization was based on Southwestern Oncology Group (SWOG) criteria. There were no differences in response rates between the 2 dose groups. The response rate was 68.5% for the 400 mg group and 67.6% for the 600 mg group. The median time to response was 12 weeks (range was 3-98 weeks) and the estimated median duration of response is 118 weeks (95% CI: 86, not reached). Adjuvant Treatment of GIST In the adjuvant setting, Gleevec was investigated in a multicenter, double-blind, placebo-controlled, randomized trial involving 713 patients (Study 1). Patients were randomized one to one to Gleevec at 400??mg/day or matching placebo for 12 months. The ages of these patients ranged from 18 to 91??years. Patients were included who had a histologic diagnosis of primary GIST, expressing KIT protein by immunochemistry and a tumor size ???3??cm in maximum dimension with complete gross resection of primary GIST within 14 to 70 days prior to registration. Recurrence-free survival (RFS) was defined as the time from date of randomization to the date of recurrence or death from any cause. In a planned interim analysis,??the median follow up was 15 months in patients without a RFS event;??there were 30 RFS events in the 12-month Gleevec arm compared to 70 RFS events in the placebo arm with a hazard ratio of 0.398 (95% CI: 0.259, 0.610), p5 cm and mitotic count >5/50 high power fields (HPF), or tumor diameter >10 cm and any mitotic count, or tumor of any size with mitotic count >10/50 HPF, or tumors ruptured into the peritoneal cavity. There were a total of 397 patients randomized in the trial with??199 patients on the 12-month treatment arm and 198 patients on the 36-month treatment arm. The median age was 61 years (range 22 to 84 years). RFS was defined as the time from date of randomization to the date of recurrence or death from any cause. The median follow-up for patients without a RFS event was 42 months. There were 84 (42%) RFS events in the 12-month treatment arm and 50 (25%) RFS events in the 36-month treatment arm. Thirty-six months of Gleevec treatment significantly prolonged RFS compared to 12 months of Gleevec treatment with a hazard ratio of 0.46 (95% CI: 0.32, 0.65), p<0.0001??(Figure 4). The median follow-up for overall survival (OS) in patients still living was 48 months. There were 25 (13%) deaths in the 12-month treatment arm and 12 (6%) deaths in the 36-month treatment arm. Thirty-six months of Gleevec treatment significantly prolonged OS compared to 12 months of Gleevec treatment with a hazard ratio of 0.45 (95% CI: 0.22, 0.89), p=0.0187 (Figure 5). Figure 4 Study 2 Recurrence-Free Survival (ITT Population) Figure 5 Study 2 Overall Survival (ITT Population)
CLINICAL PHARMACOLOGY SECTION.
12??????????CLINICAL PHARMACOLOGY 12.1??????????Mechanism of Action Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia. Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients. In vivo, imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis. Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF-mediated cellular events. In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-kit mutation. 12.3??????????Pharmacokinetics The pharmacokinetics of Gleevec have been evaluated in studies in healthy subjects and in population pharmacokinetic studies in over 900 patients. The pharmacokinetics of Gleevec are similar in CML and GIST patients. Imatinib is well absorbed after oral administration with Cmax achieved within 2-4 hours post-dose. Mean absolute bioavailability is 98%. Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately 18 and 40 hours, respectively. Mean imatinib AUC increases proportionally with increasing doses ranging from 25 mg-1,000 mg. There is no significant change in the pharmacokinetics of imatinib on repeated dosing, and accumulation is 1.5- to 2.5-fold at steady state when Gleevec is dosed once-daily. At clinically relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and ??1-acid glycoprotein. CYP3A4 is the major enzyme responsible for metabolism of imatinib. Other cytochrome P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism. The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4. It shows in vitro potency similar to the parent imatinib. The plasma AUC for this metabolite is about 15% of the AUC for imatinib. The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound. Human liver microsome studies demonstrated that Gleevec is a potent competitive inhibitor of CYP2C9, CYP2D6, and CYP3A4/5 with Ki values of 27, 7.5, and 8 ??M, respectively. Imatinib elimination is predominately in the feces, mostly as metabolites. Based on the recovery of compound(s) after an oral 14C-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose). Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites. Typically, clearance of imatinib in a 50-year-old patient weighing 50 kg is expected to be 8??L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14??L/h. The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicity.
4??????????CONTRAINDICATIONS None None (4)