• KETOVA (imatinib mesylate) is indicated for the treatment of adult patients with newly diagnosed, Philadelphia chromosome-positive, chronic myeloid leukemia (CML) in chronic phase.
  • Clinical effectiveness in newly diagnosed CML was based on progression-free survival, hematologic and cytogenetic response rates (surrogate endpoints) that are reasonably likely to predict clinical benefit in a long-term randomized controlled study.

• KETOVA (imatinib mesylate) is indicated for the treatment of pediatric patients with newly diagnosed, Philadelphia chromosome-positive, chronic myeloid leukemia (CML) in chronic phase.
  • Clinical effectiveness in newly diagnosed CML, was based on hematologic and cytogenetic response rates (surrogate endpoints) in a short-term uncontrolled study in which the majority of patients withdrew from protocol therapy to undergo hematopoietic stem cell transplantation.

• KETOVA is also indicated for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) in blast crisis or accelerated phase, or in chronic phase after failure of interferon- alpha therapy.
  • Clinical effectiveness in Philadelphia chromosome-positive chronic myeloid leukemia in blast crisis, accelerated phase or chronic phase (after failure of interferon-alpha therapy) was based on hematologic and cytogenetic response rates (surrogate endpoints), which have shown to be sustained for at least two years.

• KETOVA is also indicated for use as a single agent for induction phase therapy in adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).
  • Clinical effectiveness for use as a single agent for induction phase therapy in adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) was based on hematologic response rates (surrogate endpoints).

• KETOVA is also indicated for the treatment of adult patients with relapsed or refractory Ph+ ALL as monotherapy.
  • Clinical effectiveness in adult patients with relapsed or refractory Ph+ ALL as monotherapy was based on hematologic and cytogenetic response rates (surrogate endpoints).

• KETOVA is also indicated for the treatment of adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet derived growth factor receptor (PDGFR) gene re- arrangements.
  • Clinical effectiveness in adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re- arrangements was based on hematologic and cytogenetic response rates (surrogate endpoints).

• KETOVA is also indicated for the treatment of adult patients with aggressive sub- types of systemic mastocytosis (ASM and SM-AHNMD1) without the D816V c-Kit mutation. If c-Kit mutational status in patients with ASM or SM-AHNMD1 is not known or unavailable, treatment with KETOVA may be considered if there is no satisfactorily response to other therapies.
  • Clinical effectiveness in adult patients with aggressive sub-types of systemic mastocytosis (ASM and SM-AHNMD1) without the D816V c-Kit mutation and in adult patients with ASM or SM-AHNMD1 where c-Kit mutational status is not known or unavailable, and if there is no satisfactory response to other therapies was based on hematologic response rates (surrogate endpoints).
  • 1 ASM: Aggressive systemic mastocytosis; SM-AHNMD: Systemic mastocytosis with an associated clonal hematological non-mast-cell disorder.

• KETOVA is also indicated for the treatment of adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) with FIP1L1-PDGFRα rearrangement.
  • Clinical effectiveness in adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) with FIP1L1-PDGFRα rearrangement was based on hematologic and cytogenetic response rates (surrogate endpoints).

• KETOVA is also indicated for the treatment of adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP).
  • Clinical effectiveness in adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP) was based on objective response rate (surrogate endpoints).

Dosing Considerations

Therapy should be administered under the supervision of a physician experienced in the treatment of patients with hematological malignancies and/or malignant sarcomas .

The prescribed dose should be administered orally, during a meal and with a large glass of water to minimize the risk of gastrointestinal disturbances. 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 the morning and in the evening. Efficacy data for the 800 mg/day dose are limited.

Dosing in pediatric patients should be on the basis of body surface area (mg/m2). Treatment can be given as a once daily dose or alternatively the daily dose may be split into two administrations – one in the morning and one in the evening. (See CLINICAL TRIALS SECTION AND ACTION AND CLINICAL PHARMACOLOGY SECTION). There is no experience with the use of imatinib mesylate in pediatric patients with CML under 2 years of age. There is very limited to no experience with the use of imatinib mesylate in children in other indications.

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). Traces of the disintegrated tablet left in the glass after drinking should also be consumed.

Treatment should be continued as long as the patient continues to benefit.

For daily dosing of 800 mg, KETOVA should be administered using the 400 mg tablet twice a day to reduce exposure to iron.

Preventative measures should be considered prior to treatment with KETOVA in patients with increased risk for TLS (see WARNINGS AND PRECAUTIONS and Monitoring and Laboratory Tests).

Recommended Dose and Dosage Adjustment

Chronic myeloid leukemia (CML)

The recommended dosage of KETOVA is 400 mg/day for adult patients with newly diagnosed CML or in chronic phase CML. The recommended dosage for adult patients in accelerated phase or blast crisis is 600 mg/day. The recommended dosage of KETOVA for pediatric patients with newly diagnosed Ph+ CML is 340 mg/m2/day (rounded to the nearest 100 mg, i.e not to exceed 600 mg).

In CML, a dose increase from 400 mg to 600 mg or to 800 mg/day 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 reactions 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 12 months of treatment; or loss of a previously achieved hematologic and/or cytogenetic response.

Patients with CML should undergo regular response monitoring (See WARNINGS AND PRECAUTIONS). Any changes to patient imatinib therapy (for example, when imatinib dose is lowered due to occurrence of side effects) should be followed by close response monitoring.

Ph+ Acute Lymphoblastic Leukemia (Ph+ALL)

The recommended dose of KETOVA for use as a single-agent for induction phase therapy in adult patients with newly diagnosed Ph+ALL, or for adult patients with relapsed or refractory Ph+ ALL is 600 mg/day.

Myelodysplastic/Myeloproliferative Diseases (MDS/MPD)

The recommended dose of KETOVA is 400 mg/day for adult patients with MDS/MPD

Aggressive sub-types of Systemic Mastocytosis (ASM and SM-AHNMD)

The recommended dose of KETOVA is 400 mg/day for adult patients with ASM or SM- AHNMD without the D816V c-Kit mutation or mutational status unknown and not responding satisfactory to other therapies.

For patients with ASM or SM-AHNMD associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day is recommended. A 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.

Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL)

The recommended dose of KETOVA is 100 mg/day for adult patients with HES/CEL.

For HES/CEL patients, a dose increase from 100 mg to 400 mg may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. Treatment should be continued as long as the patient continues to benefit.

Dermatofibrosarcoma Protuberans (DFSP)

The recommended dose of KETOVA is 800 mg/day for adult patients with DFSP.

Dose Adjustment for Hepatotoxicity and Other Non-Hematologic Adverse Drug Reactions

If a severe non-hematologic adverse drug reaction develops (such as severe hepatotoxicty or severe fluid retention), KETOVA should be withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.

If elevations in bilirubin >3 x institutional upper limit of normal (IULN) or in liver transaminases >5 x IULN occur, KETOVA should be withheld until bilirubin levels have returned to a <1.5 x IULN and transaminase levels to <2.5 x IULN. In adults, treatment with KETOVA may then be continued at a reduced daily dose (i.e., from 400 mg to 300 mg or from 600 mg to 400 mg, or from 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.

Dose Adjustment for Patients with Hepatic Impairment

Patients with mild, and moderate liver dysfunction should be dosed at the minimum effective dose of 400 mg daily and patients with severe liver dysfunction should start at 200 mg daily. In the absence of severe toxicity, a dose increase up to 300 mg daily may be considered. The dose should be reduced if the patient develops unacceptable toxicity. (See ACTION AND CLINICAL PHARMACOLOGY).

Dose Adjustment for Patients with Renal Impairment

Imatinib mesylate and its metabolites are not excreted via the kidney to a significant extent. However, it has been shown that exposure to imatinib is increased up to 2-fold in patients with mild (CrCL: 40-59 mL/min) and moderate (CrCL: 20-39 mL/min) renal dysfunction, and that there is a significant correlation in the incidence of serious adverse events with decreased renal function.

In clinical trials to date, the safety and efficacy of imatinib mesylate in patients with renal impairment has not been established. Patients with mild or moderate renal dysfunction should be treated with cautio n, and be given the minimum recommended effective dose of 400 mg daily as starting dose. (SEE ACTION AND CLINICAL PHARMACOLOGY) The dose should be reduced if not tolerable. If tolerated, the dose can be increased for lack of efficacy (See section WARNINGS AND PRECAUTIONS). Treatment of patients with moderate renal insufficiency at 800 mg cannot be recommended as this dose has not been investigated in these patients. The effect of imatinib mesylate treatment on patients with severe renal dysfunction (CrCL: <20 mL/min) and on hemodialysis has not been assessed, so treatment of these patients with imatinib cannot be recommended.

Hematologic adverse drug reactions

Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in the table below.

Dose adjustments for neutropenia and thrombocytopenia

General

Effects on ability to drive and use machines

Reports of motor vehicle accidents have been received in patients receiving imatinib mesylate. Caution should be recommended when driving a car or operating machinery (see Undesirable effects from Post-Marketing reports section and Drug-Lifestyle Interactions section).

Tumour Lysis Syndrome (TLS):

Tumour lysis syndrome has occurred in patients taking imatinib mesylate, including fatal cases (see “Undesirable effects from Post-marketing Reports”). Patients at increased risk for TLS include those with tumours having a high proliferative rate (e.g. CML-blast crisis), concomitant chemotherapy or radiotherapy or having a solid tumour of large size (bulky disease), decreased kidney function or elevated lactate dehydrogenase (LDH) at baseline.

Preventative measures, including correction of clinically significant dehydration and treatment of high uric acid levels, should be considered for patients at increased risk of developing TLS (see DOSAGE AND ADMINISTRATION and Monitoring and Laboratory Tests).

Carcinogenesis and Mutagenesis

A 2-year preclinical carcinogenicity study conducted in rats demonstrated renal adenomas/carcinomas, urinary bladder and urethra papillomas, papillomas/carcinomas of the preputial and clitoral gland, adenocarcinomas of the small intestine, adenomas of the parathyroid glands, benign and malignant tumors of the adrenal medulla and papillomas/carcinomas of the nonglandular stomach (See TOXICOLOGY).

Long-term, non-neoplastic histological changes identified in the preclinical carcinogenicity study in rats include cardiomyopathy.

The relevance of these findings in the rat carcinogenicity study for humans is not known. An analysis of the clinical safety data from clinical trials and spontaneous adverse event reports did not provide evidence of an increased overall incidence of malignancies in patients treated with imatinib mesylate compared to that of the general population.

However, adverse events in cancer patients are significantly under reported and a large proportion of patients treated with imatinib mesylate have had limited follow-up thus not permitting a final analysis of the potential for an increased incidence of a secondary malignancy in patients treated with imatinib mesylate.

Cardiovascular

Severe congestive heart failure (CHF) and reduction of left ventricular ejection fraction (LVEF) have been reported in patients taking imatinib mesylate. Although several of these patients had preexisting conditions including hypertension, diabetes and prior coronary artery disease, they were subsequently diagnosed with CHF. Patients with known cardiac disease or risk factors for cardiac failure should be monitored carefully and those with symptoms or signs consistent with CHF should be evaluated and treated. In patients with history of cardiac disease or in elderly patients, a baseline evaluation of LVEF is recommended prior to initiation of KETOVA therapy.

In patients with hypereosinophilic syndrome (HES) with occult or known infiltration of HES cells within the myocardium, isolated cases of cardiogenic shock/left ventricular dysfunction believed to be associated with HES   cell degranulation upon initiation of imatinib mesylate therapy, have been reported. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib mesylate. Myelodysplastic/myeloproliferative diseases (MDS/MPD) and systemic mastocytosis (SM) might be associated with high eosinophil levels. Performance of an echocardiogram and determination of serum troponin should therefore be considered in patients with HES/CEL and in patients with MDS/MPD or ASM and SM-AHNMD associated with high eosinophil levels. These patients with HES/CEL or ASM, SM-AHNMD and MDS/MPD must be also on 1-to 2 mg/kg of prednisone equivalent oral steroids for one to two weeks, initiated at least 2 days prior to beginning KETOVA therapy.

Endocrine and Metabolism

Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during treatment with imatinib mesylate. Thyroid-Stimulating Hormone levels should be closely monitored in such patients.

Fluid Retention and edema

Imatinib mesylate is often associated with edema and occasionally serious fluid retention (see Adverse Reactions Table 1 and 2). All Grades of fluid retention/edema were reported in up to 61.7% for newly diagnosed CML patients, up to 76.2% for other CML patients across all clinical trials. Patients should be weighed and monitored regularly for signs and symptoms of fluid retention as fluid retention can occur after months of treatment. An unexpected rapid weight gain should be carefully investigated and appropriate treatment provided. The probability of edema was increased with higher imatinib dose. Severe superficial edema was reported in 1.5% of newly diagnosed CML patients taking imatinib mesylate and in 2.1% to 5.8% of other adult CML patients taking imatinib mesylate. In addition, other severe fluid retention events (e.g., pleural effusion, pericardial effusion, pulmonary edema, and ascites) were reported in 1.3% of newly diagnosed CML patients taking imatinib mesylate and in 1.7% to 6.2% of other adult CML patients taking imatinib mesylate.

Gastrointestinal

Hemorrhage: See “Hemorrhage” below.

Imatinib mesylate is sometimes associated with GI irritation. KETOVA 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.

Hematologic

Hematologic Toxicity: Treatment with imatinib mesylate is often associated with neutropenia or thrombocytopenia (See Undesirable effects, Tables 6 to 8). 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). 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 involving neutropenia (31%), thrombocytopenia (16%) and anemia (14%). These generally occur within the first several months of therapy (See DOSAGE AND ADMINISTRATION).

An increased rate of opportunistic infections was observed in a monkey study with chronic imatinib treatment. 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, where all grades of lymphopenia were observed in 0.3% patients).

Hemorrhage

All Grades of hemorrhage were reported in up to 28.9% for newly diagnosed CML patients, up to 53% for other CML patients across all clinical trials.

In the newly diagnosed CML trial, 1.8% of patients had Grades 3 /4 hemorrhage.

Subdural hematomas have been reported in association with imatinib administration in patients with other contributing factors, including older age (eg., Age greater than 50-55 years); thrombocytopenia due to the underlying malignancy or concomitant administration of multi- agent chemotherapy; concomitant administration of medications that increase bleeding risk; and prior lumbar puncture or head trauma. In clinical trials, the incidence of subdural hematoma has ranged from 0 to 2.4%.

This risk of bleeding should be evaluated carefully in all patients. Caution should be exercised with the concomitant use of antiplatelet agents or warfarin, especially in patients who are thrombocytopenic. Platelet counts and prothrombin time should be measured on a regular basis when imatinib is used concurrently with anticoagulants, prostacyclins, or other medications that increase bleeding risk. Patients should be monitored for gastrointestinal symptoms at the start of therapy and during the treatment. Patients who experience head trauma or have unexplained neurological symptoms should be evaluated for subdural hematoma. In view of a potential interaction between imatinib mesylate and warfarin leading to increased exposure to warfarin, patients who require anticoagulation with warfarin should be monitored especially closely when imatinib mesylate dose adjustments are necessary (see DRUG INTERACTIONS).

Hepatic/Biliary/Pancreatic

Liver failure: There have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some cases the outcome was fatal. One patient, who was taking acetaminophen regularly for fever along with imatinib mesylate, died of acute liver failure (see DRUG INTERACTIONS).

Hepatotoxicity: Hepatotoxicity, occasionally severe, may occur with KETOVA (see Undesirable effects Tables 1 and 2). 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 interruption and/or dose reduction of the treatment with KETOVA. (See sections Undesirable effects and DOSAGE AND ADMINISTRATION). Patients with hepatic impairment should be closely monitored. Although pharmacokinetic analysis results showed there is considerable inter-subject variation, the mean exposure to imatinib did not differ significantly between patients with mild and moderate liver dysfunction (as measured by dose normalized AUC) and patients with normal liver function. Patients with severe liver dysfunction demonstrated increased exposure to imatinib and its active metabolite CGP 74588. Liver function monitoring remains crucial as no long term toxicity and tolerability have been established (See CLINICAL PHARMACOLOGY).

Hepatotoxicity has been observed in patients treated with imatinib mesylate. All Grades of liver toxicity (including liver failure) were reported in up to 11.6% for newly diagnosed CML patients, up to 12% for other CML patients across all clinical trials.

Hepatitis B reactivation

Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.

Patients should be tested for HBV infection before initiating treatment with imatinib mesylate. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with imatinib mesylate should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8).

Toxicities From Long-Term Use:

It is important to consider potential toxicities suggested by animal studies, specifically, liver, kidney and cardiac toxicity and immunosuppression. Liver toxicity was observed in rats, dogs and cynomolgus monkeys in repeated dose studies. Most severe toxicity was noted in dogs and included elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia.

Renal

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.

Imatinib mesylate and its metabolites are not excreted via the kidney to a significant extent. Creatinine clearance (CrCL) is known to decrease with age, and age did not significantly affect imatinib kinetics.

In patients with impaired renal function, imatinib mesylate plasma exposure is higher (1.5- to 2- fold increase) than in patients with normal renal function, probably due to an elevated plasma level of alpha-acid glycoprotein (AGP), an imatinib-binding protein, in patients with renal dysfunction. As well, there is a significant correlation in the incidence of serious adverse events with decreased renal function (p=0.0096). Patients with mild or moderate  renal impairment should be treated with cautio n (see DOSAGE AND ADMINISTRATION). Since the effect of imatinib mesylate treatment on patients with severe renal dysfunction or on dialysis has not been sufficiently           assessed, recommendations on the treatment of these patients with KETOVA cannot be made. Patients with history of renal failure should be monitored carefully, and any patient with signs or symptoms consistent with  renal failure should be evaluated and treated.

Respiratory

Pulmonary events: Rare cases of pulmonary fibrosis and interstitial pneumonitis have been reported in patients who have received imatinib mesylate. However, no definitive relationship has been established between the occurrence of these pulmonary events and treatment with imatinib mesylate.

Skin

Skin and Mucosa: Although rare, Erythema multiforme (EM), Toxic epidermal Necrolysis (TEN), and Stevens Johnson syndrome (SJS) have been reported in patients who have received imatinib mesylate. Skin biopsies in some cases of exfoliative skin rash associated with imatinib mesylate use have shown a mixed cellular infiltrate characteristic of a toxic drug reaction. Severe cases of exfoliative rash may require treatment interruption or discontinuation.

Drug reaction with eosinophilia and systemic symptoms (DRESS), a potentially life-threatening syndrome including fever, severe skin eruption, lymphadenopathy, hematologic abnormalities (eosinophilia or atypical lymphocytes), and internal organ involvement, has also been reported in imatinib-treated patients. DRESS regressed when imatinib mesylate was discontinued, and in all cases where the drug was re-introduced, DRESS recurred. If DRESS occurs, KETOVA should be interrupted, and permanent discontinuation should be considered.

Special Populations:

Pediatrics:

There is no experience with the use of imatinib mesylate in pediatric patients with CML under 2 years of age. There is very limited to no experience with the use of imatinib mesylate in children in other indications.

There have been case reports and series demonstrating growth retardation in children and pre- adolescents receiving imatinib mesylate. No prospective studies have been carried out in this regard and the long term effects of prolonged treatment with imatinib mesylate on growth in children are unknown. In a juvenile toxicology study, transitory decreases in crown to rump length were observed (between days 17 and 52 post-partum) in rats administered approximately 2X the highest recommended human pediatric dose of 340 mg/m2. At this dose, shortened tibia and femur lengths were non-reversible in female rats while a trend towards reversibility was seen in male rats (see TOXICOLOGY, Juvenile Developmental Toxicology). Another study demonstrated that rats administered imatinib resulted in premature growth plate closure (see

Vandyke et al.).Therefore, close monitoring of growth in children under KETOVA is highly recommended (see Undesirable effects).

Geriatrics:

In the CML phase II studies, approximately 20% of patients were older than 65 years. The efficacy of imatinib mesylate was similar in all age groups studied.

Monitoring and Laboratory tests:

Patients with known cardiac disease or risk factors for cardiac failure should be monitored carefully and those with symptoms or signs consistent with CHF should be evaluated and treated. In patients with history of cardiac disease or in elderly patients, a baseline evaluation of LVEF is recommended prior to initiation of KETOVA therapy. (see Cardiovascular).

For patients receiving KETOVA, 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) (see Hematologic, and DOSAGE and ADMINISTRATION).

Liver function (transaminases, bilirubin, and alkaline phosphatase) should be monitored before initiation of treatment and monthly or as clinically indicated (see Hepatic/Biliary/Pancreatic, and DOSAGE and ADMINISTRATION).

Patients should be weighed and monitored regularly for signs and symptoms of fluid retention as fluid retention can occur after months of treatment with KETOVA (see Fluid Retention and edema).

Thyroid-Stimulating Hormone (TSH) levels should be closely monitored in thyroidectomy patients undergoing levothyroxine replacement during treatment with KETOVA (see Endocrine and Metabolism).

Signs and symptoms consistent with tumour lysis syndrome (e.g. hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure, elevated LDH, high fevers) should be monitored at baseline and during initial treatment with KETOVA (see Tumour Lysis Syndrome (TLS) and DOSAGE AND ADMINISTRATION).

Close monitoring of growth in children under KETOVA treatment is highly recommended (See Special Populations, Pediatrics).

During treatment with KETOVA, serum electrolytes should be regularly monitored for possible hypophosphatemia, hyperkalemia, and hyponatremia in all patients as well as glucose, blood urea nitrogen (BUN) and creatinine. In addition, in pediatric patients, serum calcium and albumin should also be regularly monitored. Grades 3 /4 hypophosphatemia have been observed in 16.5% (15% Grade 3 and 1.5% Grade 4) of patients in a phase I dose finding study 03001 (N=143) and a phase II study 0102 (N=260) of chronic myeloid leukemia in blast crisis.

In patients with CML, regular response monitoring, particularly when therapy is modified, is essential to detect early signs of loss of response so that appropriate actions can be taken to avoid disease progression. A loss of response can occur at any time, but is more likely when imatinib treatment is modified (See DOSAGE AND ADMINISTRATION).

Drug-Drug Interactions

Drugs that may alter imatinib plasma concentrations

Drugs that may increase imatinib plasma concentrations:

Substances that inhibit the cytochrome P450 isoenzyme (CYP3A4) activity may decrease metabolism and increase imatinib concentrations. There was a significant increase in exposure to imatinib (mean Cmax and AUC of imatinib increased by 26% and 40%, respectively) in healthy subjects when imatinib mesylate was co-administered with a single dose of ketoconazole (CYP3A4 inhibitor). Caution is recommended when administering KETOVA with inhibitors of the CYP3A4 family (e.g. ketoconazole, erythromycin, clarithromycin, itraconazole, grapefruit juice).

Drugs that may decrease imatinib plasma concentrations:

Substances that are inducers of CYP3A4 activity may increase metabolism and decrease imatinib plasma concentrations. Co-medications that induce CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or St. John’s Wort) may significantly reduce exposure to KETOVA.

Administration of rifampin 600 mg daily for eight days to 14 healthy adult volunteers, followed by a single 400 mg dose of imatinib mesylate increased imatinib oral dose clearance by 3.8-fold (90% CI 3.5- to 4.3-fold). Mean Cmax, AUC0-24 and AUC0-∞ decreased by 54%, 68% and 74%, respectively compared to treatment without rifampin.

Similar results were observed in patients with malignant gliomas treated with imatinib mesylate while taking enzyme-inducing anti-epileptic drugs (EIAEDs) such as carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone. The plasma AUC for imatinib decreased by 73% compared to patients not on EIADs.

In two published studies, concomitant administration of imatinib mesylate and a product containing St. John’s wort led to a 30-32% reduction in the AUC of imatinib mesylate. In patients in whom rifampin or other CYP3A4 inducers are indicated, alternate therapeutic agents with less enzyme induction potential should be considered.

Drugs that may have their plasma concentration altered by KETOVA

There is limited data on drug interactions. Since the major metabolic pathway is CYP3A4 mediated and KETOVA is an inhibitor of CYP2D6, precaution should be exercised with the co-administration of the following classes of drugs.

Table 9: Common classes of drugs used in patients with CML

Imatinib mesylate increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5- fold, respectively, suggesting an inhibition of the CYP3A4 by imatinib mesylate. Therefore, caution is recommended when administering KETOVA with CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine, pimozide), (See Undesirable effects.)

In vitro, imatinib mesylate inhibits the cytochrome P450 isoenzyme CYP2D6 activity at similar concentrations that affect CYP3A4 activity. Imatinib at 400 mg twice daily had a weak inhibitory effect on CYP2D6-mediated metoprolol metabolism, with metoprolol Cmax and AUC being increased by approximately 23%. Caution is advised for CYP2D6 substrates with a narrow therapeutic window such as metoprolol. In patients treated with KETOVA and metoprolol clinical monitoring should be considered.

In vitro data suggest that imatinib mesylate has some capacity to act as an inhibitor of CYP2C9, although at concentrations higher than would be expected in plasma with recommended doses.

However, caution should be exercised with the concomitant use of drugs metabolized by CYP2C9 (e.g. warfarin).  In view of the potential interaction between imatinib mesylate and warfarin, the international normalised ratio (INR) of patients who require anticoagulation with warfarin should be monitored closely, especially when KETOVA dose adjustments are necessary. Consideration should be given to anticoagulation with low-molecular weight heparin or unfractionated heparin.

In vitro, imatinib mesylate inhibits acetaminophen O-glucuronidation metabolic pathway with Ki value of 58.5 μmol/L. Based on the in vitro results, systemic exposure to acetaminophen would be expected to increase when co-administered with imatinib mesylate. A clinical study showed that co-administration of imatinib mesylate (400 mg/day between days two and eight) in the presence of single dose acetaminophen (1000 mg/day on day eight) in CML patients did not alter the pharmacokinetics of acetaminophen. Imatinib mesylate pharmacokinetics was also not altered in the presence of single-dose acetaminophen. However, there are no pharmacokinetic or safety data on the concomitant use of imatinib mesylate at doses > 400 mg/day or the chronic use of concomitant acetaminophen and imatinib mesylate. Hence CAUTION is recommended in patients on the concomitant use of KETOVA with acetaminophen.

Drug-Food Interactions

There were no clinically relevant differences in absorption when imatinib mesylate was administered either with food or in the fasting state. The concomitant use of grapefruit juice should be avoided.

Effects on Fertility

Stem cell factor and c-Kit genes are known to be important for germ cell development. Human studies on male patients receiving imatinib mesylate and its effect on male fertility and spermatogenesis have not been performed. However, clinical evidence of profound oligospermia with imatinib mesylate use has been reported in the literature as has clinical evidence for maintained male fertility. There is also pre-clinical evidence of impaired spermatogenesis without a reduction in fertility (See TOXICOLOGY). Therefore, physicians should advise and counsel their male patients as appropriate.

Use in Pregnancy

Teratogenicity has been observed in animals studies (See TOXICOLOGY). There are no clinical trials on the use of imatinib mesylate in pregnant women. There have been post-market reports of spontaneous abortions and infant congenital anomalies from women who have taken imatinib mesylate. Imatinib is teratogenic in animals,  therefore, KETOVA should not be administered to pregnant women. If it is used during pregnancy the patient should be apprised of the potential risk to the fetus. Women of childbearing potential must be advised to use highly effective birth control during treatment. Highly effective contraception is a method of birth control which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly.

Use in Lactation

In animals, imatinib and/or its metabolites were extensively excreted in milk. Both imatinib and its active metabolite can be distributed into human milk. There are two known cases of imatinib exposure during lactation. Their analysis shows the following results: the milk: plasma ratio was determined to be 0.5 for imatinib and 0.9 for the metabolite. Since the effects of exposure of the infant to imatinib are potentially serious, women taking KETOVA should not breast feed.

Effects on ability to drive and use machines

Reports of motor vehicle accidents have been received in patients receiving imatinib mesylate.

Patients should be advised that they may experience undesirable effects such as dizziness, blurred vision or somnolence during treatment with KETOVA. Therefore, caution should be recommended when driving a car or operating machinery.

Adverse Drug Reaction Overview

Imatinib mesylate was generally well tolerated across all studies in CML. Complications of advanced malignancies and co-administered medications make causality of adverse events difficult to assess in single arm studies. The majority of imatinib mesylate treated patients experienced adverse events at some time.

Recent published literature revealed cases of musculoskeletal pain symptoms occurring upon imatinib discontinuation following long-term treatment, with a high frequency of 18% to 46% in CML patients. Those events may persist for months and were referred to as imatinib withdrawal symptoms (IWS).

Clinical Trial Adverse Drug Reactions

Chronic Myeloid Leukemia

Imatinib mesylate was generally well tolerated with chronic oral daily dosing in patients with CML including pediatric patients. The majority of patients experienced adverse events at some point in time, however, most events were of mild to moderate Grade. In adult clinical trials, drug discontinuation for drug-related adverse events was observed in 2.4% of newly diagnosed patients, in 5 % of patients in chronic phase, 8% in accelerated phase and 9% in blast crisis.

The most frequently reported drug-related adverse events were fluid retention (superficial edema and other fluid retention events), nausea, vomiting, diarrhea, muscle cramps, fatigue and rash (Refer to Table 1 and 2 for newly diagnosed CML and other CML patients, respectively). Superficial edemas were a common finding in all studies described primarily as periorbital edemas or lower limb edemas. However, these edemas were rarely severe and may be managed with diuretics, other supportive measures, or by reducing the dose of imatinib mesylate tablets. (See DOSAGE AND ADMINISTRATION.)

Other adverse events such as pleural effusion, ascites, pulmonary edema and rapid weight gain with or without superficial edema may be collectively described as “other fluid retention events”.

These events were usually managed by withholding imatinib mesylate treatment temporarily and/or with diuretics and/or other appropriate supportive care measures. However, a few of these events may be serious or life threatening and several patients with blast crisis died with a complex clinical history of pleural effusion, congestive heart failure and renal failure. The following tables list the adverse experiences which occurred in ≥ 10% of patients in the clinical trials, regardless of relationship to therapy.

Table 1: Adverse experiences Regardless of Relationship to Study Drug reported in newly diagnosed CML (≥10% of all patients)(1)

(1) All  adverse  events  occurring  in  ≥10%  of  patients  are  listed  regardless  of  suspected  relationship to treatment.

Table 2: Adverse Experiences Regardless of Relationship to Study Drug Reported in Other CML Clinical Trials (≥10% of all patients in any trial)(1)

*Grouped Events

(1) All adverse events occurring  in  ≥10% of patients are listed regardless of suspected relationship to treatment.

(2) Other fluid retention events include pleural effusion, ascites, pulmonary edema, pericardial effusion, anasarca, edema aggravated, and fluid retention not otherwise specified.

Adverse Reactions in the Pediatric Population

The overall safety profile of imatinib mesylate treatment in 93 pediatric patients was similar to that observed in studies with adult patients. Nausea, vomiting were the most commonly reported individual adverse events with an incidence similar to that seen in adult patients. Although most patients experienced adverse events at some time during the studies, the incidence of Grade 3 / 4 adverse events was low.

Significantly higher frequencies of hypocalcemia (23.5 vs 1.1%), hyperglycemia (19.6 vs 2.9%), hypoglycemia (21.6 vs 1.5%), hypophosphatemia (19.6 vs 3.3%), hypoalbuminemia (13.7 vs 0.2%) and hyponatremia (13.7 vs 0.2%) were observed in pediatric patients compared to adult patients.

Acute Lymphoblastic Leukemia:

The adverse reactions were similar for Ph+ ALL as for CML. The most frequently reported non- hematologic drug- related adverse events were fluid retention (superficial edema and other fluid retention events), nausea, vomiting, diarrhea, muscle cramps, fatigue and rash. Superficial edemas were a common finding in all studies described primarily as periorbital edemas or lower limb edemas. However, these edemas were rarely severe and may be managed with diuretics, other supportive measures, or by reducing the dose of imatinib mesylate (See DOSAGE AND ADMINISTRATION).

Myelodysplastic/Myeloproliferative Diseases:

Adverse events, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with imatinib mesylate for MDS/MPD in Trial B2225, are shown in Table 3.

Table 3 Adverse Experiences Regardless of Relationship to Study Drug Reported (more than one patient) in MDS/MPD Patients in Trial B2225 (≥10% all patients) all Grades

Aggressive sub-types of Systemic Mastocytosis (ASM and SM-AHNMD)

All ASM patients experienced at least one adverse event at some time. The most frequently reported adverse events were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritis, rash and lower respiratory tract infection. None of the 5 patients in Study B2225 with ASM discontinued imatinib mesylate due to drug-related adverse events or abnormal laboratory values.

Hypereosinophilic Syndrome and Chronic Eosinophilic Leukemia

The overall safety profile in this HES/CEL small patient population does not seem different from the known safety profile of imatinib mesylate observed in other larger populations of hematologic malignancies, such as CML. However, in patients with HES and cardiac involvement, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated with the initiation of imatinib mesylate therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures and temporarily withholding imatinib mesylate (see WARNINGS and PRECAUTIONS). All patients experienced at least one adverse event, the most common being gastrointestinal, cutaneous and musculoskeletal disorders. Hematologic abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia and anemia.

Dermatofibrosarcoma Protuberans

Adverse events, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with imatinib mesylate for DFSP in Trial B2225 are shown in Table 4.

Table 4 Adverse Experiences Regardless of Relationship to Study Drug Reported in DFSP Patients in Trial B2225 (≥10% all patients) all Grades

Adverse Drug Reactions in clinical studies for CML

The following adverse reactions as applicable are ranked under headings of frequency, the most frequent first, using the following convention: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000), including isolated reports. Adverse reactions reported below are based on the registration studies for CML. Frequencies are determined by reported related events according to the investigator.

Cardiovascular

Common: 

Flushing¹

Uncommon: 

Palpitations, cardiac failure congestive (on a patient-year basis, cardiac events including congestive heart failure were more commonly observed in patients with transformed CML than in patients with chronic CML), pulmonary edema, tachycardia, hypertension¹, hematoma¹, hypotension¹, peripheral coldness¹, Raynaud’s phenomenon¹

Rare: 

Arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion

Clinical laboratory Tests (See Tables 5, 6 and 8)

Uncommon:

Blood CPK increased, blood LDH increased

Rare: 

Blood amylase increased

Dermatologic

Common:

Pruritus, face edema, dry skin, erythema, alopecia, photosensitivity reaction

Uncommon:

Rash pustular, sweating increased, urticaria, increased tendency to bruise, exfoliative dermatitis, onychoclasis, folliculitis, petechie, psoriasis, bullous eruption, nail disorder, skin pigmentation changes, purpura, palmar-plantar erythrodysaesthesia  syndrome

Rare:

Nail discolouration, vesicular rash, erythema multiforme, leucocytoclastic vasculitis, Stevens- Johnson syndrome, acute generalized exanthematous pustulosis (AGEP), acute febrile neutrophilic dermatosis (Sweet’s syndrome)

Digestive

Common:

Flatulence, abdominal distension, gastroesophageal reflux, dry mouth, gastritis

Uncommon:

Stomatitis, mouth ulceration, eructation, malaena, oesophagitis, ascites, gastric ulcer, hematemesis, cheilitis, dysphagia, pancreatitis

Rare:

Colitis, ileus, inflammatory bowel disease

General Disorders and Administration Site Conditions

Common:

Weakness, anasarca, chills, rigors

Uncommon:

Chest pain, malaise

Hematologic (See tables 6 and 7)

Common:

Pancytopenia, febrile neutropenia

Uncommon:

Thrombocythemia, lymphopenia, eosinophilia, lymphadenopathy

Rare:

Aplastic anemia, hemolytic anemia

Hepatobiliary disorders

Uncommon:   

Jaundice, hepatitis, hyperbilirubinemia

Rare:              

Hepatic failure, hepatic necrosis (some fatal cases of hepatic necrosis have been reported)

Hypersensitivity

Rare:              

Angioedema

Infections

Uncommon:   

Sepsis, herpes simplex, herpes zoster, sinusitis, cellulitis, influenza, urinary tract infection, gastroenteritis

Rare:

Fungal infection

Not known:    

Hepatitis B reactivation

Metabolic and nutritional

Common:         

Anorexia, weight decreased

Uncommon:   

Hypophosphatemia, dehydration, gout, appetite disturbances, hyperuricemia, hypercalcemia, hyperglycemia, hyponatremia

Rare:                

Hyperkalemia, hypomagnesemia

Musculoskeletal

Common:         

Joint swelling

Uncommon:     

Joint and muscle stiffness

Rare:

Muscular weakness, arthritis

Nervous system/psychiatric

Common:           

Paresthesia, taste disturbance, hypoesthesia

Uncommon:   

Depression², libido decrease, syncope, peripheral neuropathy, somnolence, migraine, memory impairment, sciatica, restless leg syndrome, tremor

Rare:                  

Increased intracranial pressure, confusion, convulsions, optic neuritis

Neoplasm benign, malignant and unspecified (including cysts and polyps)

Uncommon:       

Tumor lysis syndrome

Renal

Uncommon:       

Renal pain, renal failure acute, urinary frequency increased, hematuria

Reproductive

Uncommon:       

Erectile dysfunction, breast enlargement, menorrhagia, menstruation irregular, sexual dysfunction, nipple pain, scrotal edema

Respiratory

Common:           

Dyspnea, epistaxis, cough

Uncommon:   

Pleural effusion (pleural effusion was reported more commonly in patients with transformed CML (CML-AP and CML-BC) than in patients with chronic CML), pharyngolaryngeal pain, pharyngitis

Rare:              

Pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary hemorrhage

Special senses

Common:       

Eyelid edema, lacrimation increased, conjunctival hemorrhage, conjunctivitis, dryeye, vision blurred

Uncommon:   

Eye irritation, eye pain, orbital edema, scleral hemorrhage, retinal hemorrhage, blepharitis, macular edema, vertigo, tinnitus, hearing loss

Rare:                  

Cataract, papilledema, glaucoma

¹Vascular disorders (hematoma was most common in patients with transformed CML (CML-AP and CML-BC).

²Depression may lead to suicide ideation and/or suicide attempts.

Second malignancies in imatinib mesylate -treated patients:

Table 5: Observed and expected numbers of cases of second malignancies (excluding non- melanoma skin cancer) in clinical trials

(1) Expected in the general population

SIR: Standardized incidence ratio

The numbers of cancers reported in the clinical trials were similar to those expected in the general population. The observed numbers of cases for all cancers, prostate cancer and urinary bladder cancer were slightly lower than those expected in the general population, while the number of observed kidney cancer cases was slightly higher (3 compared to 2.26 expected cases respectively). In all cases, the differences were not statistically significant.

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory test abnormalities in CML clinical trials

Cytopenias, and particularly neutropenia and thrombocytopenia, have been a consistent finding in all studies, with the suggestion of a higher frequency at doses ≥ 750 mg (phase I study). However, the occurrence of cytopenias was also clearly dependent on the stage of the disease.

In patients with newly diagnosed CML, cytopenias were less frequent than in other CML patients (Tables 6 and 7).

The frequency of Grade 3 or 4 neutropenia (ANC <1.0x109/L) and thrombocytopenia (platelet count <50x109/L) were higher in blast crisis and accelerated phase (36-48% and 32-33% for neutropenia and thrombocytopenia, respectively, Table 7) as compared to chronic phase CML (27% neutropenia and 21% thrombocytopenia). In chronic phase CML a Grade 4 neutropenia (ANC <0.5x109/L) and thrombocytopenia (platelet count <10x109/L) were observed in 9% and <1% of patients, respectively. The median duration of the neutropenic and thrombocytopenic episodes ranged usually from 2 to 3 weeks, and from 3 to 4 weeks, respectively. These events can usually be managed with either a reduction of the dose or an interruption of treatment with imatinib mesylate, but can, in  rare cases, lead to permanent discontinuation of treatment. (see WARNINGS and PRECAUTIONS for Hematologic Toxicity).

Severe elevation of transaminases or bilirubin has been seen in <5% CML patients and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately one week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. There have been cases of hepatic necrosis and cholestatic hepatitis and hepatic failure; in some of which outcome was fatal (See DRUG INTERACTIONS).

Table 6: Newly occurring Grades 3/4 biochemical toxicities in newly diagnosed CML patients

* p<0.001 (Difference in Grade 3 + Grade 4 abnormalities between the two treatment groups).

Table 7: Laboratory test abnormalities in other CML clinical trials

CTC grades: neutropenia (grade 3 ≥0.5 - 1.0 x 109/L), grade 4 <0.5 x 109/L), thrombocytopenia (grade 3 ≥10 - 50 x 109/L, grade 4 <10 x 109/L), anemia (hemoglobin ≥65 - 80 g/L, grade 4 <65 g/L), elevated creatinine (grade 3 >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).

Clinically relevant or severe abnormalities of the 12 patients treated with imatinib mesylate for DFSP in Trial B2225 are presented in Table 8.

Table 8: Laboratory Abnormalities Reported in DFSP Patients in Trial B2225 

Adverse Reactions from Post-Marketing Reports

The following types of ADRs have been reported from post-marketing experience and from additional clinical studies with imatinib mesylate. They include spontaneous case reports as well as serious ADRs from smaller or ongoing clinical studies and the expanded access programs. Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to imatinib mesylate exposure.

Cardiovascular: thrombosis/embolism¹, pericarditis, cardiac tamponade, anaphylactic shock¹ subdural hematoma1

Dermatology: lichenoid keratosis, lichen planus, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic syndroms (DRESS)

Digestive: ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation (some fatal cases of gastrointestinal perforation have been reported) Diverticulitis

General: motor vehicle accidents

Hepatic: Hepatitis, Hepatotoxicity with fatal outcomes (see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS)

Hepatitis B reactivation : Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see WARNINGS AND PRECAUTIONS).

Musculoskeletal: avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children

Nervous system/psychiatric: cerebral edema (including fatalities)

Reproductive: Hemorrhagic corpus luteum/hemorrhagic ovarian cyst

Respiratory: acute respiratory failure (fatal cases have been reported in patients with advanced disease, severe infections, severe neutropenia and other serious concomitant conditions), interstitial lung disease

Special senses: vitreous hemorrhage

Neoplasm benign, malignant and unspecified (including cysts and polyps): Tumor lysis syndrome, some of which were fatal.

¹Vascular disorders.

-  To report any side effect(s)

Experience with higher than therapeutic doses is limited. Isolated cases of imatinib mesylate overdosage have been reported spontaneously and in the literature. Generally the reported outcome in these cases was improvement or recovery. In the event of overdosage the patient should be observed and appropriate symptomatic treatment should be given.

Events that have been reported at different dose ranges are as follows:

Adult overdose:

1,200 to 1,600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhea, rash, erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite, increased bilirubin and liver transaminase level.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): A case report in the literature about one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increased transaminases. 8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Pediatric overdose:

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

Pharmacotherapeutic group: Protein kinase inhibitor

ATC code: L01XE01

KETOVA (imatinib mesylate) is a protein tyrosine kinase inhibitor, which inhibits the Bcr-Abl tyrosine kinase at the  in vitro, cellular, and in vivo levels. The compound selectively inhibits proliferation and induces apoptosis in Bcr-Abl positive cell lines as well as fresh leukemic cells from Philadelphia chromosome-positive chronic myeloid leukemia (CML) and acute lymphoid leukemia (ALL) patients. In colony formation assays using ex vivo peripheral blood and bone marrow samples, imatinib shows selective inhibition of Bcr-Abl positive colonies from CML patients.

In vivo, it 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.

In addition, imatinib is an inhibitor of several receptor tyrosine kinases: the platelet-derived growth factor receptors (PDGFR-α and PDGFR-β), and the stem cell factor (SCF), receptor (c- Kit), and it inhibits the cellular events mediated by these receptors.

Constitutive activation of the PDGFR or the Abl protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutive production of PDGF have been implicated in the pathogenesis of several conditions including MDS/MPD, HES/CEL and DFSP. In addition, constitutive activation of c-Kit or the PDGFR has been implicated in the pathogenesis of SM. Imatinib inhibits signaling and proliferation of cells driven by dysregulated PDGFR, Kit and Abl kinase activity.

Several mechanisms of resistance have been identified from in vitro studies of Bcr-Abl positive cell lines. Mechanisms include amplification of the Bcr-Abl gene and overexpression of the multidrug resistance P- glycoprotein. Mutation or amplification of the Bcr-Abl gene has been described in relapsed patients with advanced stage CML.

Prevalence of Abl kinase domain mutations among samples of resistant CML patients varies across studies, likely reflecting variations in time frames for testing, the duration of imatinib exposure, patient selection differences, and perhaps differences in techniques and sensitivity.

The specific clinical relevance of Abl kinase domain mutations in the prognosis and management of patients with CML requires further study. It is likely that mutations will have different clinical phenotypes, with some being subject to higher-dose imatinib therapy, depending on the IC50 of the mutation, and others requiring alternative treatment strategies.

Recent in-vitro experiments have indicated that some mutations remain sensitive to imatinib mesylate at high concentrations, other mutants remain unresponsive to dose escalation, which may indicate a kinase-independent, or even Bcr-Abl independent mechanisms of resistance.

Currently identified possible mechanisms of resistance to imatinib mesylate can be categorized in two main groups: the mechanisms where Bcr-Abl is reactivated and cell proliferation remains dependent on Bcr-Abl signaling, and mechanisms where the Bcr-Abl protein remains inactivated by imatinib mesylate but alternative signalling pathways become activated. Whereas the primary resistance to imatinib mesylate seems mostly associated with amplification of the Bcr-Abl gene, secondary resistance (ie. loss of response or progression) appears to be associated with the emergence of mutations of the Bcr-Abl gene (see below):

Currently identified mechanisms of resistance to imatinib

P-gP: Protein–glyco-Protein

MDR: Multidrug Resistance

AGP: Alpha 1-acid glycoprotein

The clinical utility of detecting mutations remains to be demonstrated, since mutations have been described among imatinib mesylate treated patients without evidence of disease progression. In addition, the approach to managing resistance will differ by CML disease stage, irrespective of treatment. Clinical and molecular resistance is much more prevalent among patients with blast crisis and accelerated phase CML, than among patients with chronic phase CML.

The pharmacokinetics (PK) of imatinib mesylate have been evaluated in 591 patients and 33 healthy subjects over a dosage range of 25 to 1000 mg.

Absorption: Mean absolute bioavailability for the capsule formulation is 98%. The coefficient of variation for plasma imatinib AUC is in the range of 40-60% after an oral dose. When given with a high fat meal the rate of absorption of imatinib was reduced (11% decrease in Cmax and prolongation of tmax by 1.5 h), with a small reduction in AUC (7.4%) compared to fasting conditions.

Distribution: At clinically relevant concentrations of imatinib, binding to plasma proteins is approximately 95% on the basis of in vitro experiments, mostly to albumin and ∞1-acid glycoprotein, with little binding to lipoproteins.

In in vitro experiments, the active metabolite, CGP74588, exhibited similar protein binding behaviour to imatinib at clinically relevant concentrations.

Metabolism: 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 and the terminal half-life is approximately 40 h at steady state. The plasma protein binding of the N-demethylated metabolite CGP74588 was shown to be similar to that of the parent compound in both healthy volunteers and Acute Myeloid Leukemia (AML) patients although there were variabilities in blood distribution and protein binding between AML patients. Some of the AML patients showed a significantly higher unbound fraction of both compounds which led to a higher blood cell uptake.

A phase I study has shown a 4- to 7-fold accumulation of the metabolite CGP74588 at steady state following once daily dosing, which was greater than the parent drug (See below: plasma pharmacokinetics). This might be due to the fact that CGP74588 is metabolized at a 53% lower metabolic conversion rate compared to imatinib mesylate in human hepatocytes. The reduced metabolic clearance of CGP74588 is further implied by in vitro experiments which showed a lower infinity of CGP74588 to CYP3A4 in comparison to STI571.

Excretion: Based on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81% of the dose was eliminated within 7 days in 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.

Plasma pharmacokinetics: Following oral administration in healthy volunteers, the t½ was approximately 18 hours suggesting that once daily dosing is appropriate. Plasma pharmacokinetic profiles were analyzed in CML patients on Day 1 and on either Day 7 or 28, by which time plasma concentrations had reached steady state. The increase in mean imatinib AUC with increasing dose was linear and dose proportional in the range 25-1000 mg  after oral administration. There was no change in the kinetics of imatinib on repeated dosing, and accumulation is 1.5-2.5 fold at steady state when imatinib mesylate is dosed once daily.

The effect of body weight on the clearance of imatinib is such that for a patient weighing 50 kg the mean clearance is expected to be 8.5 l/h, while for a patient weighing 100 kg the clearance will rise to 11.8 l/h. These changes are not considered sufficient to warrant dose adjustment based on body weight. There is no effect of gender on the kinetics of imatinib.

Special Populations and Conditions:

Pediatrics: A total of 31 pediatric patients with either chronic phase CML (n=15), CML in blast crisis (n = 4) or acute leukemias (n=12) have been enrolled in a dose-escalation phase I trial. In this trial the effective dose in pediatric patients was not identified. This was a population of heavily pretreated patients; 45% had received prior BMT and 68% prior multi-agent chemotherapy. Newly diagnosed patients or those eligible for bone marrow transplantation were not studied. The median age was 14 years (range 3 to 20 years). Of the 31 patients, n=12  were three to 11 years old at the start of the study, n= 17 were between 12 and 18 years, and only two were more than 18 years old. Patients were treated with doses of imatinib mesylate of 260 mg/m2/day (n=6), 340 mg/m2/day (n=11), 440 mg/m2/day (n= 8) and 570 mg/m2/day (n=6). Dosing based upon body surface area resulted in some patients receiving higher than the adult therapeutic dose, and the effect of this on pediatric patient safety is limited.

As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients in both phase I and phase II studies. Dosing in children at 260 and 340 mg/m2/day achieved similar exposure, respectively, as  doses of 400 mg and 600 mg in adult patients, although this was based upon a small sample size. The comparison of AUC0-24 on Day 8 versus Day 1 at the 340 mg/m2/day dose level revealed a 1.7- fold drug accumulation after repeated once daily dosing. As in adults, there was considerable inter-patient variability in the pharmacokinetics, and the coefficient of variation for AUC0-24 ranged from 21% (260 mg/m2/day) to 68% (570 mg/m2/day). The AUC did not increase proportionally with dose within the range of doses examined. The active metabolite, GCP 74588, contributed about 20% of the AUC for imatinib. Total plasma clearance is about 8 - 10 L/h at steady state. The plasma AUC of imatinib is significantly lower (p=0.02) in children at ages between 2 and <12 years old (29.3 ug*hr/mL) than those at ages between 12 and <20 years old (34.6 ug*hr/mL). However, the difference between  the two age groups does not seem to be clinically significant, only 15% of difference (geometric mean of 29.3 in children compared to 34.6 in adolescents). The AUC exposure in both age groups falls within the adult AUC(0-24h) range, between 24.8 and 39.7 μg*h/ml, achieved at 400 mg and 600 mg daily doses, respectively.

Geriatrics: Based on population PK analysis, there was an effect of age on the volume of distribution (12% increase in patients > 65 years old). This change is not thought to be clinically significant.

Hepatic Insufficiency: In a study of patients with mild and moderate hepatic dysfunction (Table 10), the mean exposure to imatinib (dose normalized AUC) did not differ significantly compared with patients with normal liver function. There was a tendency toward an increased exposure in patients with severe liver dysfunction (approximately 45% increase compared with patients with normal liver function). In this study up to 500 mg daily was used in patients with mild liver dysfunction, up to 400 mg daily in patients with moderate, and up to 300 mg daily in patients with severe liver dysfunction.

In the severe liver dysfunction group 29% of patients experienced serious adverse events at the 100 mg dose level, 60% at the 200 mg and 50% of patients treated at the 300 mg dose levels. (See sections WARNINGS and PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Table 10: Liver Dysfunction Classification

ULN=upper limit of normal for the institution

SGOT= serum glutamic oxaloacetic transferase

Renal Insufficiency: Imatinib and its metabolites are not excreted via the kidney to a significant extent.

In a study of patients with varying degrees of renal dysfunction (mild, moderate and severe – see Table 11 below for renal function classification), the mean exposure to imatinib (dose normalized AUC) increased 1.5- to 2-fold compared to patients with normal renal function, which corresponded to an elevated plasma level of AGP, a protein to which imatinib binds strongly. There was a correlation with the incidence of serious adverse events and decreasing renal function (p = 0.0096). In this study, 800 mg daily was used in patients with mild renal dysfunction and 600 mg daily was used in patients with moderate renal dysfunction. The 800 mg dose was not tested in patients with moderate renal dysfunction due to the limited number of patients enrolled. Similarly, only 2 patients with severe renal dysfunction were enrolled at the low (100 mg) dose, and no higher doses were tested. No patients on hemodialysis were enrolled in the study. Since the effect of imatinib mesylate treatment on patients with severe renal dysfunction and on hemodialysis has not been sufficiently assessed, treatment of these patients with imatinib cannot be recommended. Patients with mild or moderate renal dysfunction should be treated with cautio n, and be given the minimum recommended dose of 400 mg daily as starting dose. The dose should be reduced if not tolerable. If tolerated, the dose can be increased for lack of efficacy. Dosing of patients with moderate renal insufficiency at 800 mg cannot be recommended as this has not been investigated (See sections Undesirable effects; DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS).

Table 11: Renal function classification

CrCL = Creatinine Clearance

Drug-Drug Interactions

CYP3A4 Inhibitors: There was a significant increase in exposure to imatinib (mean Cmax and AUC increased by 26% and 40%, respectively) in healthy subjects when imatinib mesylate was coadministered with a single dose of ketoconazole (a CYP3A4 inhibitor). (See DRUG INTERACTIONS).

CYP3A4 Substrates: Imatinib increased the mean Cmax and AUC of simvastatin (CYP3A4 substrate) by 2- and 3.5- fold, respectively, indicating an inhibition of CYP3A4 by imatinib. (See DRUG INTERACTIONS).

CYP3A4 Inducers: Administration of rifampin 600 mg daily for eight days to 14 healthy adult volunteers, followed by a single 400 mg dose of imatinib mesylate increased imatinib oral dose clearance by 3.8-fold (90% CI 3.5- to 4.3-fold). Mean Cmax, AUC0-24 and AUC0-∞ decreased by 54%, 68% and 74%, respectively compared to treatment without rifampin. In patients in whom rifampin or other CYP3A4 inducers are indicated, alternate therapeutic agents with less enzyme induction potential should be considered. (See DRUG INTERACTIONS).

In vitro Studies of CYP Enzyme Inhibition: Human liver microsome studies demonstrated that imatinib is a potent competitive inhibitor of CYP2C9, CYP2D6, and CYP3A4/5 with Ki values of 27, 7.5, and 8 μM, respectively. Imatinib is likely to increase the blood level of drugs that are substrates of CYP2C9, CYP2D6 and CYP3A4/5. (See DRUG INTERACTIONS).

Acute Toxicity

Doses higher than 100 mg/kg were not administered due to the limited solubility of imatinib at neutral pH. The compound was well tolerated at both the low and mid dose. However, there was one death at the high dose (out of ten rats treated) which occurred 30 minutes post-dose. Death was attributed to lung injury, most probably as a result of precipitation of the compound in the pulmonary microcirculation. No other treatment-related changes were noted. Based on these results, 30 mg/kg is considered to be the maximum dose of STI571 which can be administered by slow i.v. bolus injection to rats without causing symptoms.

Subacute and Chronic Toxicity

The toxicity after i.v. bolus administration was qualitatively similar to that seen after oral dosing. Irritation at the injection site was seen after peripheral i.v. administration in most studies using this route of administration.

Mild to moderate hematological changes were observed in rats, dogs and monkeys at oral doses ≥ 20, 10 and 75 mg/kg, respectively. Red blood cells were generally affected at doses slightly lower than those causing a decrease of white blood cell formation. Bone marrow changes reflected the effects on peripheral blood in rats and dogs. Atrophy of lymphoid organs, lymphocytolysis and/or lymphoid depletion were observed at oral doses ≥ 200 mg/kg in the rat and ≥ 30 mg/kg in the dog. A slight to moderate reduction in spermatogenesis was observed in the dog ≥ 30 mg/kg and in the rat fertility study at a dose of 60 mg/kg.

Enlarged corpora lutea with hemorrhagic fluid were observed in rats at doses ≥ 60 mg/kg and in dogs at 100→50 mg/kg/day. Diarrhea was observed in the dog at oral doses ≥ 3mg/kg/day. Emesis was observed at oral doses of ≥ 30 mg/kg in the dog and ≥ 75 mg/kg in the monkey. Atrophy of the intestinal mucosa, vacuolar degeneration of the gastrointestinal epithelium and single cell necrosis were observed at doses ≥ 10 mg/kg in the dog and at 600 mg/kg in the rat. The effects on bone marrow, lymphoid tissues, testis/ovaries, and gastrointestinal (GI) tract can be explained by an exaggerated pharmacological effect of imatinib on its different molecular targets.

The kidney was a target organ in rats and monkeys. In rats, hyperplasia of the transitional epithelium in the renal papilla and in the urinary bladder was observed at doses ≥ 6 mg/kg without changes in serum or urinary parameters. These findings may reflect local irritation of the compound to the urinary tract, since it has shown to be a local moderate irritant after i.v. administration. In monkeys, focal mineralisation and dilatation of renal tubules, and tubular nephrosis was seen in a 2-week oral dose range finding study at 150→100 mg/kg.

Biochemical changes indicating renal dysfunction (increased BUN and creatinine, electrolyte changes) were noted.

The liver was a target organ in rats and dogs. Increases in transaminases, and decreases in cholesterol, triglycerides, total protein and albumin were observed in both species. Liver toxicity was greater in dogs, as reflected by more extensive microscopic findings consisting of mild multifocal hepatocellular necrosis (single cell type) and single cell necrosis in bile ducts with reactive hyperplasia, and/or inflammation adjacent to blood vessels and bile ducts at doses ≥ 10 mg/kg, most pronounced at the100/50 mg/kg/day. After the recovery period, liver lesions were more severe than in the main study, associated with peribiliary fibrosis and increased incidence and severity of bile duct hyperplasia. Antinucleolar antibodies located in hepatocytes and in epithelial bile duct cells were detected in the 4-week dog exploratory study.

Reproductive Toxicity Studies

Reproductive toxicity studies indicated that imatinib has a teratogenic potential in rats at doses ≥ 30 mg/kg. A dose of 10 mg/kg appeared to represent the no effect level (NOEL). In rats, doses ≥30 mg/kg induced embryo- fetal toxicity and/or teratogenicity (exencephaly, encephalocele, absent or reduced frontal, parietal and/or interparietal bones; dose-dependent protruded tongues) in surviving fetuses. In rabbits, there was no evidence  of teratogenicity. Although testes and epididymal weights and percent motile sperm were decreased in male rats at 60 mg/kg, there were no effects on mating or on the number of pregnant females.

Three groups of time-pregnant female rats (n=24/group) were administered STI571 orally by gavage at dosages of 5, 15 and 45 mg/kg/day. The animals were treated from gestation day 6 through lactation day 20.

There was no maternal mortality. A red vaginal discharge was noted in the 45 mg/kg/day group on either day 14 or 15 of gestation. At this dose the number of stillborn pups was slightly increased while the number of viable pups and the number of pups dying between postpartum days 0 and 4 were decreased. In the F1 offspring, at the same dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters achieving criterion for preputial separation was slightly decreased. F1 fertility was not affected while an   increased number of resorptions and a decreased number of viable fetuses was noted at 45 mg/kg/day. The No Effect Level (NOEL) for both the maternal animals and the F1 generation was 15 mg/kg/day (one-fourth the maximum human dose of 800 mg/day).

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 imatinib mesylate.

Human studies on male patients receiving imatinib mesylate and its effect on male fertility and spermatogenesis have not been performed. Male patients concerned about their fertility on imatinib mesylate treatment should consult with their physician.

Juvenile Developmental Toxicology

No new target organs were identified in the rat juvenile development toxicology study (day 10 to 70 post- partum). In the juvenile toxicology study, transitory effects upon growth and delay in vaginal opening and preputial separation were observed at approximately 0.3 to 2 times the average pediatric exposure at the highest recommended dose of 340 mg/m2. Also, mortality was observed in juvenile animals (around weaning phase) at approximately 2-times the average pediatric exposure at the highest recommended dose of 340 mg/m2.

Carcinogenesis and Mutagenesis

The genotoxic potential of imatinib was assessed in a battery of mutagenicity tests:

Imatinib was devoid of genotoxicity in bacterial and cellular assays for mutagenic effects. The rat micronucleus assay which detects clastogenic and aneugenic effects was also negative. Positive results were obtained in an in vitro assay for clastogenicity (chromosome aberration) in the presence of metabolic activation, but only at concentrations which resulted in significant cytotoxicity.

In a 2-year rat carcinogenicity study, imatinib was administered in feed at doses of 15, 30 and 60 mg/kg/day, and resulted in a statistically significant reduction in the longevity of males rats at 60 mg/kg/day and females rats at

≥30 mg/kg/day. Histopathological examination of decedents revealed cardiomyopathy (both rats sexes), chronic progressive nephropathy (females rats) and preputial gland papilloma as principal causes of death or reasons for sacrifice. Target organs for neoplastic changes were the kidneys, urinary bladder, urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-glandular stomach. The no observed effect levels (NOEL) for the various target organs with neoplastic lesions were established as follows: 30 mg/kg/day for the kidneys, urinary bladder, urethra, small intestine, parathyroid glands, adrenal glands and non-glandular stomach, and 15 mg/kg/day for the preputial and clitoral gland.

The papilloma/carcinoma of the preputial/clitoral gland were noted at 30 and 60 mg/kg/day in rats, representing (approximately 0.5 to 4 times the human daily exposure at 400 mg/day (based on AUC), 0.3 to 2.4 times the human daily exposure at 800 mg/day (based on AUC), and 0.4 to 3.0 times the daily exposure in children at 340 mg/m2 (based on AUC). The renal adenoma/carcinoma, the urinary bladder and urethra papilloma, 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 only at 60 mg/kg/day.

Non-neoplastic histological lesions not identified in earlier preclinical studies were the cardiovascular system, pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and dilatation, leading to signs of cardiac insufficiency in some animals.

Not applicable.

Store below 30°C.

If your doctor or pharmacist tells you to stop taking this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.