Imatinib Mesylate

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-[4methyl-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 less than or equal to 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).

Experience with doses greater than 800 mg is limited. Isolated cases of Gleevec overdose have been reported. In the event of overdosage, observe the patient and give appropriate supportive treatment.

Adult Overdose

Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite.

Weakness, myalgia, increased CPK, increased bilirubin, gastrointestinal pain.

One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases.

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-yearold male exposed to a single dose of 980 mg experienced decreased white blood cell count and diarrhea.

Imatinib interferes with the growth of some cancer cells.

Imatinib is used to treat a certain types of leukemia (blood cancer) such as Philadelphia chromosome positive chronic myeloid leukemia (CML). It is also used to treat certain tumors of the stomach and digestive system.

Imatinib may also be used for purposes not listed in this medication guide.

Do not use imatinib if you are pregnant. It could harm the unborn baby.

Before using this medication, tell your doctor if you have liver disease, kidney disease, underactive thyroid, congestive heart failure, a history of stomach ulcer or bleeding, or if you are receiving chemotherapy.

Take this medicine with a large glass of water.

Imatinib should be taken with a meal. Do not take the medicine on an empty stomach.

If you miss a dose, take the medicine as soon as you remember, making sure you also eat a meal and drink a large glass of water. Skip the missed dose if it is almost time for your next meal. Do not take extra medicine to make up the missed dose.

To be sure this medication is not causing harmful effects, your blood may need to be tested often. Your liver function may also need to be tested. Visit your doctor regularly.

Take the missed dose as soon as you remember, making sure you also eat a meal and drink a large glass of water. Skip the missed dose if it is almost time for your next meal. Do not take extra medicine to make up the missed dose.

The following serious adverse reactions are described elsewhere in the labeling:

• Fluid Retention and Edema [see WARNINGS AND PRECAUTIONS]
• Hematologic Toxicity [see WARNINGS AND PRECAUTIONS]
• Congestive Heart Failure and Left Ventricular Dysfunction [see WARNINGS AND PRECAUTIONS]
• Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
• Hemorrhage [see WARNINGS AND PRECAUTIONS]
• Gastrointestinal Disorders [see WARNINGS AND PRECAUTIONS]
• Hypereosinophilic Cardiac Toxicity [see WARNINGS AND PRECAUTIONS]
• Dermatologic Toxicities [see WARNINGS AND PRECAUTIONS]
• Hypothyroidism [see WARNINGS AND PRECAUTIONS]
• Growth Retardation in Children and Adolescents [see WARNINGS AND PRECAUTIONS]
• Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
• Impairments Related to Driving and Using Machinery [see WARNINGS AND PRECAUTIONS]
• Renal Toxicity [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The majority of Gleevec-treated patients experienced adverse reactions at some time. 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 IFN+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]. 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. These reactions may be serious or life threatening.

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 IFN+Ara-C Study (greater than or equal to 10% of Gleevec Treated Patients)(1)

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 (greater than or equal to 10% in Gleevec 400 mg Once-Daily or nilotinib 300 mg Twice-Daily Groups) 60-Month Analysisa

Table 4: Adverse Reactions Regardless of Relationship to Study Drug Reported in Other CML Clinical Trials (greater than or equal to 10% of All Patients in any Trial)(1) Myeloid Blast Crisis Accelerated Phase Chronic Phase, IFN Failure

Cytopenias, and particularly neutropenia and thrombocytopenia, were a consistent finding in all studies, with a higher frequency at doses greater than or equal to 750 mg (Phase 1 study). The occurrence of cytopenias in CML patients was also dependent on the stage of the disease.

In patients with newly diagnosed CML, cytopenias were less frequent than in the other CML patients (see Tables 5, 6, and 7). The frequency of Grade 3 or 4 neutropenia and thrombocytopenia was between 2-and 3-fold higher in blast crisis and accelerated phase compared to chronic phase (see Tables 4 and 5). The median duration of the neutropenic and thrombocytopenic episodes varied from 2 to 3 weeks, and from 2 to 4 weeks, respectively.

These reactions can usually be managed with either a reduction of the dose or an interruption of treatment with Gleevec, but may require permanent discontinuation of treatment.

Table 5: Laboratory Abnormalities in Newly Diagnosed CML Clinical Trial (Gleevec versus IFN+Ara-C)

Table 6: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities in the Newly Diagnosed CML Clinical Trial (Gleevec versus nilotinib)

Table 7: Laboratory Abnormalities in Other CML Clinical Trials

Severe elevation of transaminases or bilirubin occurred in approximately 5% of CML patients (see Tables 6 and 7) and were usually managed with dose reduction or interruption (the median duration of these episodes was approximately 1 week). Treatment was discontinued permanently because of liver laboratory abnormalities in less than 1.0% of CML patients. One patient, who was taking acetaminophen regularly for fever, died of acute liver failure. In the Phase 2 GIST trial, Grade 3 or 4 SGPT (ALT) elevations were observed in 6.8% of patients and Grade 3 or 4 SGOT (AST) elevations were observed in 4.8% of patients. Bilirubin elevation was observed in 2.7% of patients.

Single Agent Therapy

The overall safety profile of pediatric patients treated with Gleevec in 93 children studied was similar to that found in studies with adult patients, except that musculoskeletal pain was less frequent (20.5%) and peripheral edema was not reported. Nausea and vomiting were the most commonly reported individual adverse reactions with an incidence similar to that seen in adult patients. Most patients experienced adverse reactions at some time during the study. The incidence of Grade 3/4 events across all types of adverse reactions was 75%; the events with the highest Grade 3/4 incidence in CML pediatric patients were mainly related to myelosuppression.

In Combination With Multi-agent Chemotherapy

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 study population included patients with a median age of 10 years (1 to 21 years), 61% of whom were male, 75% were white, 7% were black and 6% were Asian/Pacific Islander. Patients with Ph+ ALL (n=92) were assigned to receive Gleevec and treated in 5 successive cohorts. Gleevec exposure was systematically increased in successive cohorts by earlier introduction and more prolonged duration.

The safety of Gleevec given in combination with intensive chemotherapy was evaluated by comparing the incidence of grade 3 and 4 adverse events, neutropenia (less than 750/mcL) and thrombocytopenia (less than 75,000/mcL) in the 92 patients with Ph+ ALL compared to 65 patients with Ph-ALL enrolled on the trial who did not receive Gleevec. The safety was also evaluated comparing the incidence of adverse events in cycles of therapy administered with or without Gleevec. The protocol included up to 18 cycles of therapy. Patients were exposed to a cumulative total of 1425 cycles of therapy, 778 with Gleevec and 647 without Gleevec. The adverse events that were reported with a 5% or greater incidence in patients with Ph+ ALL compared to Ph-ALL or with a 1% or greater incidence in cycles of therapy that included Gleevec are presented in Table 8.

Table 8: Adverse Reactions Reported More Frequently in Patients Treated with Study Drug (greater than 5%) or in Cycles with Study Drug (greater than 1%)

In older patients (greater than or equal to 65 years old), with the exception of edema, where it was more frequent, there was no evidence of an increase in the incidence or severity of adverse reactions. In women there was an increase in the frequency of neutropenia, as well as Grade 1/2 superficial edema, headache, nausea, rigors, vomiting, rash, and fatigue. No differences were seen that were related to race but the subsets were too small for proper evaluation.

The adverse reactions were similar for Ph+ ALL as for Ph+ CML. The most frequently reported drug-related adverse reactions reported in the Ph+ ALL studies were mild nausea and vomiting, diarrhea, myalgia, muscle cramps and rash. Superficial edema was a common finding in all studies and were described primarily as periorbital or lower limb edemas. These edemas were reported as Grade 3/4 events in 6.3% of the patients and may be managed with diuretics, other supportive measures, or in some patients by reducing the dose of Gleevec.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the patients treated with Gleevec for MDS/MPD in the Phase 2 study, are shown in Table 9.

Table 9: Adverse Reactions Regardless of Relationship to Study Drug Reported (More than One Patient) in MPD Patients in the Phase 2 Study (greater than or equal to 10% All Patients) All Grades

All ASM patients experienced at least one adverse reaction at some time. The most frequently reported adverse reactions were diarrhea, nausea, ascites, muscle cramps, dyspnea, fatigue, peripheral edema, anemia, pruritus, rash and lower respiratory tract infection. None of the 5 patients in the Phase 2 study with ASM discontinued Gleevec due to drug-related adverse reactions or abnormal laboratory values.

The safety profile in the HES/CEL patient population does not appear to be different from the safety profile of Gleevec observed in other hematologic malignancy populations, such as Ph+ CML. All patients experienced at least one adverse reaction, the most common being gastrointestinal, cutaneous and musculoskeletal disorders. Hematological abnormalities were also frequent, with instances of CTC Grade 3 leukopenia, neutropenia, lymphopenia, and anemia.

Adverse reactions, regardless of relationship to study drug, that were reported in at least 10% of the 12 patients treated with Gleevec for DFSP in the Phase 2 study are shown in Table 10.

Table 10: Adverse Reactions Regardless of Relationship to Study Drug Reported in DFSP Patients in the Phase 2 Study (greater than or equal to 10% All Patients) All Grades

Clinically relevant or severe laboratory abnormalities in the 12 patients treated with Gleevec for DFSP in the Phase 2 study are presented in Table 11.

Table 11: Laboratory Abnormalities Reported in DFSP Patients in the Phase 2 Study

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]. 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 Greater than or Equal to 10% in any One Group (Full Analysis Set) in the Phase 3 Unresectable and/or Malignant Metastatic GIST Clinical Trials

Clinically relevant or severe abnormalities of routine hematologic or biochemistry laboratory values were not reported or evaluated in the Phase 3 GIST trials. Severe abnormal laboratory values reported in the Phase 2 GIST trial are presented in Table 13.

Table 13: Laboratory Abnormalities in the Phase 2 Unresectable and/or Malignant Metastatic GIST Trial

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 (greater than or equal to 5% of Gleevec Treated Patients)(1)

Table 15: Adverse Reactions Regardless of Relationship to Study Drug by Preferred Term All Grades and 3/4 Grades (greater than or equal to 5% of Gleevec Treated Patients) Study 2(1)

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, Raynaud’s 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, eosinophilia

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

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.

Infections: hepatitis B virus reactivation1

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], 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, musculoskeletal pain upon treatment discontinuation (including myalgia, pain in extremity, arthalgia, bone pain)

Reproduction Disorders: hemorrhagic corpus luteum/hemorrhagic ovarian cyst

1Including some fatalities

Read the entire FDA prescribing information for Gleevec (Imatinib Mesylate)

Storage

Oral

Tight container at 25°C (may be exposed to 15–30°C).1 Protect from moisture.1