IMALEK

Imatinib is a small molecule kinase inhibitor.

Imatinib mesylate film-coated tablets are supplied as 100 mg and 400 mg tablets for oral administration.

Each 100 mg tablet contains 119.5 mg of imatinib mesylate equivalent to 100 mg of imatinib free base.

Each 400 mg tablet contains 478 mg of imatinib mesylate equivalent to 400 mg of imatinib free base.

Imatinib mesylate is designated chemically as 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]benzamide methanesulfonate and its structural formula is: Imatinib mesylate is a white to off-white crystalline powder.

Its molecular formula is

C 29 H 31 N 7 O.

• CH 4 SO and its molecular weight is 589.7 g/mol.

Imatinib mesylate is freely soluble in water and freely to sparingly soluble in methanol.

Ingredients: colloidal silicon dioxide (NF); crospovidone (NF); and magnesium stearate (NF).

Tablet coating: ferric oxide red (NF); ferric oxide yellow (NF); hypromellose (USP); hydroxypropyl cellulose, and polyethylene glycol (NF).

• Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase.

• Patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in blast crisis (BC), accelerated phase (AP), or in chronic phase (CP) after failure of interferon-alpha therapy.

• Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

• Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy.

• Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements.

• Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown.

• Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown.

• Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP).

• Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST).

• Adjuvant treatment of adult patients following resection of Kit (CD117) positive GIST. 1.1 Newly Diagnosed Philadelphia Positive Chronic Myeloid Leukemia (Ph+ CML) Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. 1.2 Ph+ CML in Blast Crisis (BC), Accelerated Phase (AP) or Chronic Phase (CP) After Interferon-alpha (IFN) Therapy Patients with Philadelphia chromosome positive chronic myeloid leukemia in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. 1.3 Adult Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Adult patients with relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). 1.4 Pediatric Patients With Ph+ Acute Lymphoblastic Leukemia (ALL) Pediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. 1.5 Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) Adult patients with myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor (PDGFR) gene re-arrangements. 1.6 Aggressive Systemic Mastocytosis (ASM) Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown. 1.7 Hypereosinophilic Syndrome (HES) and/or Chronic Eosinophilic Leukemia (CEL) Adult patients with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (mutational analysis or fluorescence in situ hybridization [FISH] demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown. 1.8 Dermatofibrosarcoma Protuberans (DFSP) Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans. 1.9 Kit+ Gastrointestinal Stromal Tumors (GIST) Patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors. 1.10 Adjuvant Treatment of GIST Adjuvant treatment of adult patients following complete gross resection of Kit (CD117) positive GIST.

Lactation History of heart disease Cardiopathies

Hepatotoxic chemotherapy Female likely to be pregnant Pregnancy Hepatitis B Hyperuricaemia Hepatic impairment Renal impairment Presence of anti-HBc antibodies Elderly Subject at risk of heart failure Subject at risk of renal failure Subject under 18 Subject on high dose chemotherapy Thyroidectomy, history Extended treatment.

Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML.

Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia.

Imatinib inhibits colony formation in assays using ex vivo peripheral blood and bone marrow samples from CML patients.

In vivo, imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells as well as BCR-ABL positive leukemia lines derived from CML patients in blast crisis.

Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF.

• and SCF-mediated cellular events.

In vitro, imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-Kit mutation. 12.3 Pharmacokinetics The pharmacokinetics of imatinib mesylate have been evaluated in studies in healthy subjects and in population pharmacokinetic studies in over 900 patients.

The pharmacokinetics of imatinib mesylate are similar in CML and GIST patients.

Imatinib is well absorbed after oral administration with C max achieved within to 4 hours post-dose.

Mean absolute bioavailability is 98%.

Mean imatinib

AUC increases proportionally with increasing doses ranging from 25 mg to 1,000 mg. There is no significant change in the pharmacokinetics of imatinib on repeated dosing, and accumulation is 1.5.

• to 2.5-fold at steady state when imatinib mesylate is dosed once daily.

At clinically relevant concentrations of imatinib, binding to plasma proteins in in vitro experiments is approximately 95%, mostly to albumin and α1-acid glycoprotein.

CYP3A4 is the major enzyme responsible for metabolism of imatinib.

Other cytochrome

P450 enzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, play a minor role in its metabolism.

The main circulating active metabolite in humans is the N-demethylated piperazine derivative, formed predominantly by CYP3A4.

It shows in vitro potency similar to the parent imatinib.

The plasma

AUC for this metabolite is about 15% of the AUC for imatinib.

The plasma protein binding of N-demethylated metabolite CGP74588 is similar to that of the parent compound.

Imatinib elimination is predominately in the feces, mostly as metabolites.

Based on the recovery of compound(s) after an oral 14 C-labeled dose of imatinib, approximately 81% of the dose was eliminated within 7 days, in feces (68% of dose) and urine (13% of dose).

Unchanged imatinib accounted for 25% of the dose (5% urine, 20% feces), the remainder being metabolites.

Following oral administration in healthy volunteers, the elimination half-lives of imatinib and its major active metabolite, the N-demethyl derivative (CGP74588), are approximately and 40 hours, respectively.

Typically, clearance of imatinib in a 50-year-old patient weighing 50 kg is expected to be 8 L/h, while for a 50-year-old patient weighing 100 kg the clearance will increase to 14 L/h.

The inter-patient variability of 40% in clearance does not warrant initial dose adjustment based on body weight and/or age but indicates the need for close monitoring for treatment-related toxicity.

The effect of hepatic impairment on the pharmacokinetics of both imatinib and its major metabolite, CGP74588, was assessed in 84 patients with cancer and varying degrees of hepatic impairment at imatinib doses ranging from 100 mg to 800 mg. Exposure to both imatinib and CGP74588 was comparable between each of the mildly and moderately hepatically-impaired groups and the normal group.

Patients with severe hepatic impairment tend to have higher exposure to both imatinib and its metabolite than patients with normal hepatic function.

At steady state, the mean C max /dose and AUC/dose for imatinib increased by about 63% and 45%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function.

The mean

C max /dose and AUC/dose for CGP74588 increased by about 56% and 55%, respectively, in patients with severe hepatic impairment compared to patients with normal hepatic function.

Dose reductions are necessary for patients with severe hepatic impairment.

The effect of renal impairment on the pharmacokinetics of imatinib was assessed in 59 cancer patients with varying degrees of renal impairment at single and steady state imatinib doses ranging from to 800 mg/day. The mean exposure to imatinib (dose normalized AUC) in patients with mild and moderate renal impairment increased 1.5.

• to 2-fold compared to patients with normal renal function.

AUCs did not increase for doses greater than 600 mg in patients with mild renal impairment.

AUCs did not increase for doses greater than 400 mg in patients with moderate renal impairment.

Two patients with severe renal impairment were dosed with 100 mg/day and their exposures were similar to those seen in patients with normal renal function receiving 400 mg/day. Dose reductions are necessary for patients with moderate and severe renal impairment.

As in adult patients, imatinib was rapidly absorbed after oral administration in pediatric patients, with a C max of to 4 hours.

Apparent oral clearance was similar to adult values (11.0 L/hr/m in children vs 10.0 L/hr/m in adults), as was the half-life (14.8 hours in children vs 17.1 hours in adults).

Dosing in children at both 260 mg/m and 340 mg/m 2 achieved an AUC similar to the 400 mg dose in adults.

The comparison of AUC on

Day 8 vs Day at 260 mg/m and 340 mg/m 2 dose levels revealed a 1.5.

• and 2.2-fold drug accumulation, respectively, after repeated once-daily dosing.

AUC did not increase proportionally with increasing dose.

Based on pooled population pharmacokinetic analysis in pediatric patients with hematological disorders (CML, Ph+ ALL, or other hematological disorders treated with imatinib), clearance of imatinib increases with increasing BSA.

After correcting for the

BSA effect, other demographics, such as age, body weight, and body mass index did not have clinically significant effects on the exposure of imatinib.

The analysis confirmed that exposure of imatinib in pediatric patients receiving 260 mg/m 2 once daily (not exceeding 400 mg once daily) or 340 mg/m 2 once daily (not exceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or 600 mg once daily.

Drug Interaction Studies Clinical Studies Agents Inducing CYP3A Metabolism Pretreatment of healthy volunteers with multiple doses of rifampin followed by a single dose of imatinib mesylate tablets, increased imatinib mesylate oral-dose clearance by 3.8-fold, which significantly (p less than 0.05) decreased mean C max and AUC.

Similar findings were observed in patients receiving to 1200 mg/day imatinib mesylate tablets concomitantly with enzyme-inducing anti-epileptic drugs (EIAED) (e.g., carbamazepine, oxcarbamazepine, phenytoin, fosphenytoin, phenobarbital, and primidone).

The mean dose normalized AUC for imatinib in the patients receiving EIAED’s decreased by 73% compared to patients not receiving EIAED.

Concomitant administration of imatinib mesylate tablets and St.

John’s Wort led to a 30% reduction in the AUC of imatinib.

Consider alternative therapeutic agents with less enzyme induction potential in patients when rifampin or other CYP3A4 inducers are indicated.

Imatinib mesylate tablets doses up to 1200 mg/day (600 mg twice daily) have been given to patients receiving concomitant strong CYP3A4 inducers.

CYP3A Metabolism There was a significant increase in exposure to imatinib (mean C max and AUC increased by 26% and 40%, respectively) in healthy subjects when imatinib mesylate tablets were coadministered with a single dose of ketoconazole (a CYP3A4 inhibitor).

Caution is recommended when administering imatinib mesylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole).

Grapefruit juice may also increase plasma concentrations of imatinib and should be avoided.

Interactions with Drugs Metabolized by

CYP3A4 Imatinib mesylate tablets increase the mean C max and AUC of simvastatin (CYP3A4 substrate) 2.

• and 3.5-fold, respectively, suggesting an inhibition of the CYP3A4 by imatinib mesylate.

Particular caution is recommended when administering imatinib mesylate tablets with CYP3A4 substrates that have a narrow therapeutic window (e.g., alfentanil, cyclosporine, diergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, or tacrolimus).

Imatinib mesylate tablets will increase plasma concentration of other CYP3A4 metabolized drugs (e.g., triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase inhibitors, etc).

Because warfarin is metabolized by

CYP2C9 and CYP3A4, patients who require anticoagulation should receive low-molecular weight or standard heparin instead of warfarin.

CYP2D6 Imatinib mesylate tablets increased the mean C max and AUC of metoprolol by approximately 23% suggesting that imatinib mesylate has a weak inhibitory effect on CYP2D6-mediated metabolism.

No dose adjustment is necessary, however, caution is recommended when administering imatinib mesylate tablets with CYP2D6 substrates that have a narrow therapeutic window.

Coadministration of imatinib mesylate tablets (400 mg/day for eight days) with acetaminophen (1,000 mg single dose on Day 8) in patients with CML did not result in any changes in the pharmacokinetics of acetaminophen.

Imatinib mesylate pharmacokinetics were not altered in the presence of single-dose acetaminophen.

There is no pharmacokinetic or safety data on the concomitant use of imatinib mesylate tablets at doses greater than 400 mg/day or the chronic use of concomitant acetaminophen and imatinib mesylate tablets.

P450 (CYP450) Enzymes: Imatinib inhibits CYP2C9 and CYP2D6.

Imatinib is a substrate of BCRP, P-gp, OATP1A2, OATP1B3, and OCT1.

Imatinib inhibits

Mechanism of action

Imatinib is a small chemical molecule inhibiting tyrosine kinase protein which potently inhibits the activity of tyrosine kinase (TK) BCR-ABL, as well as several TK receptors: Kit, the CWS receptor ( Stem Cell Factor ) encoded by the c-Kit proto-oncogen, the discoidin domain receptors (DDR1 and DDR2), the CSF-1R (receptor of the Colony Stimulating Factor) and the PDGF alpha and beta receptors ( Platelet-Derived Growth Factor: PDGFR-alpha and PDGFR-beta).

Imatinib can also inhibit the cellular processes mediated by the activation of the cellular processes of the receptors physicists physicists physicists physicists physicists physicists physicists physicists physicists physicists physicists physicists physicists physicists physicists.

• Hypercalcaemia (Uncommon)
• Eosinophilia (Uncommon)
• Hyponatremia (Uncommon)
• Blood creatinine (increase) (Uncommon)
• LDH (increase) (Uncommon)
• Alkaline phosphates (increase) (Uncommon)
• Hypophosphataemia (Uncommon)
• Hyperglycaemia (Uncommon)
• KPC (increase) (Uncommon)
• Liver enzymes (increase) (Common)
• Neutropenia (Very common)
• Hyperuricaemia (Uncommon)
• Hypokalaemia (Uncommon)
• Hyperbilirubinaemia (Uncommon)
• Hypomagnesaemia (Rare)
• Amylasemia (increase) (Rare)
• Hyperkalaemia (Rare)
• Transaminases (increase)
• Liver status (abnormality)
• Tumor lysis syndrome (Rare)
• Tumor necrosis Urticaria (Uncommon)
• Alopecia (Common)
• Dry skin (Common)
• Dermatitis (Very common)
• Photosensitivity (Common)
• Mucite (Uncommon)
• Bully dermatosis (Uncommon)
• Eczema (Very common)
• Pustulous eruption (Uncommon)
• Hypotrithythmia (Uncommon)
• Ecchymotic trend (Uncommon)
• Purpura (Uncommon)
• Cellulite (Uncommon)
• Exfoliative dermatitis (Uncommon)
• Hypomelanosis (Uncommon)
• Rash (Very common)
• Pétechie (Uncommon)
• Pruritus (Common)
• Panniculitis (Uncommon)
• Night sweating (Common)
• Follicleitis (Uncommon)
• Hypersudation (Uncommon)
• Psoriasis (Uncommon)
• Skin hyperpigmentation (Uncommon)
• Skin Erythema (Common)
• Onychoclasia (Uncommon)
• Pemphigus (Rare)
• Polymorphic Erythema (Rare)
• Nail discolouration (Rare)
• Generalised acute exanthemous pusulosis (Rare)
• Sweet's syndrome (Rare)
• Stevens-Johnson Syndrome (Rare)
• Vesicular rash (Rare)
• Lichen plan Toxic epidermal necrolysis Palmoplantary Erythrodysaesthesia
• Lichenoid keratosis Erythema noise Fatigue (Very common)
• Frisher (Common)
• Edema (Very common)
• Face edema (Common)
• Sexual disorder (Uncommon)
• Chest pain (Uncommon)
• Fever (Common)
• Weakness (Common)
• Anasarque (Common)
• Lower limb edema Gynecomastia (Uncommon)
• Breast volume (increase) (Uncommon)
• Menorrhagia (Uncommon)
• Menstrual irregularity (Uncommon)
• Nipple pain (Uncommon)
• Hemorrhagic ovarian Kyste (Rare)
• Yellow body haemorrhage (Rare)
• Hematoma (Uncommon)
• Febrile neutropenia (Common)
• Anemia (Very common)
• Pancytopenia (Common)
• Cardiac aplasia (Uncommon)
• Haemorrhage (Common)
• Thrombocytopenia (Very common)
• Echymosis (Uncommon)
• Lymphopenia (Uncommon)
• Contusion (Uncommon)
• Lymphadenopathy (Uncommon)
• Thrombocytosis (Uncommon)
• Haemolytic anaemia (Rare)
• Tumor haemorrhage Cytopenia Hepatitis (Uncommon)
• Ictery (Uncommon)
• Hepatic impairment (Rare)
• Liver necrosis (Rare)
• Hepatitis B (reactivation)
• Cholestatic hepatitis Cytolytic hepatitis fulminant hepatitis Acute hepatic impairment
• Oedema of Quincke (Rare)
• DRESS syndrome Anaphylactic shock Infectious Cellulitis (Uncommon)
• Mycosis (Rare)
• Flu (Uncommon)
• Zona (Uncommon)
• Herpes (Uncommon)
• Septicaemia (Uncommon)
• Water inflation (Very common)
• Dehydration (Uncommon)
• Weight (increase) (Very common)
• Drop (Uncommon)
• Weight (decrease) (Common)
• Appetite increased (Uncommon)
• Appetite decreased (Uncommon)
• Dysphagia (Uncommon)
• Anorexia (Common)
• Pseudoporphyria Eye irritation (Uncommon)
• Orbitary edema (Uncommon)
• Lacrymal hyposecretion (Common)
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• Lacrimal hypersecretion (Common)
• Periorbital edema (Very common)
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• Optical neurosis (Rare)
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• Hemorrhage of the glazed body Stomatitis (Uncommon)
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• Pharyngo-laryngyngeal pain (Uncommon)
• Sinusitis (Uncommon)
• Vertigo (Uncommon)
• Feeling dizzy (Common)
• Hyposialia (Common)
• Epistaxis (Common)
• Oral dryness (Common)
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• Pharyngitis (Uncommon)
• Libido (decrease) (Uncommon)
• Insomnia (Common)
• Depression (Uncommon)
• Anxiety (Uncommon)
• Mental confusion (Rare)
• Hypertension (Uncommon)
• Raynaud's syndrome (Uncommon)
• Malaise (Uncommon)
• Hypotension (Uncommon)
• Palpitation (Uncommon)
• Cooling of the ends (Uncommon)
• Syncope (Uncommon)
• Congestive puff (Common)
• Tachycardia (Uncommon)
• Congestive heart failure (Uncommon)
• Arrhythmia (Rare)
• Angor (Rare)
• Leukocytoclase vasculitis (Rare)
• Cardiac arrest (Rare)
• Myocardial infarction (Rare)
• Pericardial efanchement (Rare)
• Thrombotic microangiopathy (Rare)
• Atrial fibrillation (Rare)
• Pericarditis Tamponnade
• Thrombosis Embolie Ball-down (Common)
• Gastritis (Common)
• Nausea (Very common)
• Vomiting (Very common)
• Erunation (Uncommon)
• Gastrointestinal haemorrhage (Uncommon)
• Dyspepsia (Very common)
• Gastroenteritis (Uncommon)
• Ascite (Uncommon)
• Pancreatitis (Uncommon)
• Esophagitis (Uncommon)
• Diarrhoea (Very common)
• Abdominal pain (Very common)
• Hematemesis (Uncommon)
• Gastroesophageal reflux (Common)
• Melena (Uncommon)
• Constipation (Common)
• Flatulence (Common)
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• Ileus (Rare)
• Collision (Rare)
• Inflammatory abdominal pathology (Rare)
• Diverticulitis
• Intestinal occlusion Gastrointestinal perforation Gastric vascular ectasia Joint wrinkler (Uncommon)
• Joint swelling (Common)
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• Muscle spasm (Very common)
• Cramp (Very common)
• Osteonecrosis (Uncommon)
• Bone pain (Very common)
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• Growth retardation Memory Disorder (Uncommon)
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• Headache (Very common)
• Restless leg syndrome (Uncommon)
• Convulsions (Rare)
• Intracranial hypertension (Rare)
• Brain edema Pulmonary edema (Uncommon)
• Cough (Common)
• Upper respiratory tract infection (Uncommon)
• Pneumonia (Uncommon)
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• Pulmonary hypertension (Rare)
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• Interstitial pneumopathy Acute respiratory impairment Scrotum edema (Uncommon)
• Erection disorder (Uncommon)
• Pollakiuria (Uncommon)
• Haematuria (Uncommon)
• Acute renal impairment (Uncommon)
• Renal pain (Uncommon)
• Urinary tract infection (Uncommon)
• Chronic renal impairment.

Experience with doses greater than 800 mg is limited.

Isolated cases of imatinib mesylate overdose have been reported.

In the event of overdosage, observe the patient and give appropriate supportive treatment.

Overdose to 1,600 mg (duration varying between to 10 days) : Nausea, vomiting, diarrhea, rash erythema, edema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache, decreased appetite. 1,800 to 3,200 mg (as high as 3,200 mg daily for 6 days) : Weakness, myalgia, increased CPK, increased bilirubin, GI pain. 6,400 mg (single dose) : One case in the literature reported one patient who experienced nausea, vomiting, abdominal pain, pyrexia, facial swelling, neutrophil count decreased, increase transaminases. 8 to 10 g (single dose): Vomiting and GI 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 imatinib mesylate (imatinib as free base) 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 (imatinib as free base) without recurrence of adverse reactions.

Another patient developed severe muscle cramps after taking 1,600 mg of imatinib mesylate (imatinib as free base) 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 (imatinib as free base), took 800 mg of imatinib mesylate (imatinib as free base) on Day and 1,200 mg (imatinib as free base) on Day 2.

Therapy was interrupted, no adverse reactions occurred and the patient resumed therapy.

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

Adults with

Ph+ CML CP: 400 mg/day Adults with Ph+ CML AP or BC: 600 mg/day Pediatrics with Ph+ CML CP: 340 mg/m 2 /day Adults with Ph+ ALL: 600 mg/day Pediatrics with Ph+ ALL 340 mg/m 2 /day Adults with MDS/MPD: 400 mg/day Adults with ASM: 100 mg/day or 400 mg/day Adults with HES/CEL: 100 mg/day or 400 mg/day Adults with DFSP: 800 mg/day Adults with metastatic and/or unresectable GIST: 400 mg/day Adjuvant treatment of adults with GIST: 400 mg/day Patients with mild to moderate hepatic impairment: 400 mg/day Patients with severe hepatic impairment: 300 mg/day All doses of imatinib mesylate tablets should be taken with a meal and a large glass of water.

Doses of 400 mg or 600 mg (imatinib as free base) should be administered once daily, whereas a dose of 800 mg (imatinib as free base) should be administered as 400 mg (imatinib as free base) twice a day. Imatinib mesylate tablets can be dissolved in water or apple juice for patients having difficulty swallowing.

Daily dosing of 800 mg (imatinib as free base) and above should be accomplished using the 400 mg tablet (imatinib as free base) to reduce exposure to iron. 2.1 Drug Administration The prescribed dose should be administered orally, with a meal and a large glass of water.

Doses of 400 mg or 600 mg (imatinib as free base) should be administered once daily, whereas a dose of 800 mg (imatinib as free base) should be administered as 400 mg (imatinib as free base) twice a day. For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of water or apple juice.

The required number of tablets should be placed in the appropriate volume of beverage (approximately 50 mL for a 100-mg tablet, and 200 mL for a 400-mg tablet) and stirred with a spoon.

The suspension should be administered immediately after complete disintegration of the tablet(s).

For daily dosing of 800 mg (imatinib as free base) and above, dosing should be accomplished using the 400-mg (imatinib as free base) tablet to reduce exposure to iron.

Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity. 2.2 Adult Patients With Ph+ CML CP, AP, or BC The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) for adult patients in chronic phase CML and 600 mg/day (imatinib as free base) for adult patients in accelerated phase or blast crisis.

In CML, a dose increase from 400 mg to 600 mg (imatinib as free base) in adult patients with chronic phase disease, or from 600 mg to 800 mg (imatinib as free base) (given as 400 mg twice daily) in adult patients in accelerated phase or blast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after to 12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response. 2.3 Pediatric Patients With Ph+ CML CP The recommended dose of imatinib mesylate tablets for children with newly diagnosed Ph+ CML is 340 mg/m 2 /day (imatinib as free base) (not to exceed 600 mg).

Imatinib mesylate tablets treatment can be given as a once daily dose or the daily dose may be split into two–one portion dosed in the morning and one portion in the evening.

There is no experience with imatinib mesylate treatment in children under 1 year of age. 2.4 Adult Patients With Ph+ ALL The recommended dose of imatinib mesylate tablets is 600 mg/day (imatinib as free base) for adult patients with relapsed/refractory Ph+ ALL. 2.5 Pediatric Patients With Ph+ ALL The recommended dose of imatinib mesylate tablets to be given in combination with chemotherapy to children with newly diagnosed Ph+ ALL is 340 mg/m 2 /day (not to exceed 600 mg).

Imatinib mesylate tablets treatment can be given as a once daily dose. 2.6 Adult Patients With MDS/MPD Determine PDGFRb gene rearrangements status prior to initiating treatment.

The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) for adult patients with MDS/MPD. 2.7 Adult Patients With ASM Determine D816V c-Kit mutation status prior to initiating treatment.

The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) for adult patients with ASM without the D816V c-Kit mutation.

If c-Kit mutational status is not known or unavailable, treatment with imatinib mesylate tablets 400 mg/day (imatinib as free base) may be considered for patients with ASM not responding satisfactorily to other therapies.

For patients with

ASM associated with eosinophilia, a clonal hematological disease related to the fusion kinase FIP1L1-PDGFRα, a starting dose of 100 mg/day (imatinib as free base) is recommended.

Dose increase from 100 mg to 400 mg (imatinib as free base) for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. 2.8 Adult Patients With HES/CEL The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) for adult patients with HES/CEL.

HES/CEL patients with demonstrated FIP1L1-PDGFRα fusion kinase, a starting dose of 100 mg/day (imatinib as free base) is recommended.

Dose increase from 100 mg to 400 mg (imatinib as free base) for these patients may be considered in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy. 2.9 Adult Patients With DFSP The recommended dose of imatinib mesylate tablets is 800 mg/day (imatinib as free base) for adult patients with DFSP. 2.10 Adult Patients With Metastatic and/or Unresectable GIST The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) for adult patients with unresectable and/or metastatic, malignant GIST.

A dose increase up to 800 mg daily (imatinib as free base) (given as 400 mg twice daily) may be considered, as clinically indicated, in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions. 2.11 Adult Patients With Adjuvant GIST The recommended dose of imatinib mesylate tablets is 400 mg/day (imatinib as free base) for the adjuvant treatment of adult patients following complete gross resection of GIST.

In clinical trials, one year of imatinib mesylate tablets and three years of imatinib mesylate tablets were studied.

In the patient population defined in

Study 2, three years of imatinib mesylate tablets is recommended.

The optimal treatment duration with imatinib mesylate tablets is not known. 2.12 Dose Modification Guidelines Concomitant Strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers should be avoided (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampacin, phenobarbital).

If patients must be coadministered a strong CYP3A4 inducer, based on pharmacokinetic studies, the dosage of imatinib mesylate tablets should be increased by at least 50%, and clinical response should be carefully monitored.

Patients with mild and moderate hepatic impairment do not require a dose adjustment and should be treated per the recommended dose.

A 25% decrease in the recommended dose should be used for patients with severe hepatic impairment.

Patients with moderate renal impairment (creatinine clearance [CrCL] = 20 to 39 mL/min) should receive a 50% decrease in the recommended starting dose and future doses can be increased as tolerated.

Doses greater than 600 mg (imatinib as free base) are not recommended in patients with mild renal impairment (CrCL = 40 to 59 mL/min).

For patients with moderate renal impairment doses greater than 400 mg (imatinib as free base) are not recommended.

Imatinib should be used with caution in patients with severe renal impairment.

A dose of 100 mg/day was tolerated in two patients with severe renal impairment. 2.13 Dose Adjustment for Hepatotoxicity and Non-Hematologic Adverse Reactions If elevations in bilirubin greater than 3 times the institutional upper limit of normal (IULN) or in liver transaminases greater than 5 times the IULN occur, imatinib mesylate tablets should be withheld until bilirubin levels have returned to a less than 1.5 times the IULN and transaminase levels to less than 2.5 times the IULN.

In adults, treatment with imatinib mesylate tablets may then be continued at a reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg, or 800 mg to 600 mg (imatinib as free base).

In children, daily doses can be reduced under the same circumstances from 340 mg/m 2 /day to 260 mg/m 2 /day (imatinib as free base).

If a severe non-hematologic adverse reaction develops (such as severe hepatotoxicity or severe fluid retention), imatinib mesylate tablets should be withheld until the event has resolved.

Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event. 2.14 Dose Adjustment for Hematologic Adverse Reactions Dose reduction or treatment interruptions for severe neutropenia and thrombocytopenia are recommended as indicated in Table 1.

Table 1: Dose Adjustments for Neutropenia and Thrombocytopenia ASM associated with eosinophilia (starting dose 100 mg) ANC 1 less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L 1.

Stop imatinib mesylate until

ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L 2.

Resume treatment with imatinib mesylate at previous dose (i.e., dose before severe adverse reaction) HES/CEL with FIP1L1-PDGFRα fusion kinase (starting dose 100 mg) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L 1.

Resume treatment with imatinib mesylate at previous dose (i.e., dose before severe adverse reaction) Chronic Phase CML (starting dose 400 mg) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L 1.

ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L MDS/MPD, ASM and HES/CEL (starting dose 400 mg) GIST (starting dose 400 mg) 2.

Resume treatment with imatinib mesylate at the original starting dose of 400 mg 3.

If recurrence of

ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step and resume imatinib mesylate at a reduced dose of 300 mg Ph+ CML: Accelerated Phase and Blast Crisis (starting dose 600 mg) Ph+ ALL (starting dose 600 mg) ANC less than 0.5 x 10 9 /L and/or platelets less than 10 x 10 9 /L 1.

Check if cytopenia is related to leukemia (marrow aspirate or biopsy) 2.

If cytopenia is unrelated to leukemia, reduce dose of imatinib mesylate to 400 mg 3.

If cytopenia persists 2 weeks, reduce further to 300 mg 4.

If cytopenia persists 4 weeks and is still unrelated to leukemia, stop imatinib mesylate until ANC greater than or equal to 1 x 10 9 /L and platelets greater than or equal to 20 x 10 9 /L and then resume treatment at 300 mg DFSP (starting dose 800 mg) ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L 1.

ANC greater than or equal to 1.5 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L. 2.

Resume treatment with imatinib mesylate at 600 mg 3.

In the event of recurrence of

ANC less than 1 x 10 9 /L and/or platelets less than 50 x 10 9 /L, repeat step and resume imatinib mesylate at reduced dose of 400 mg. Pediatric ne.

Each imatinib mesylate film-coated tablet contains 100 mg or 400 mg of imatinib free base. 100 mg Tablets Brownish orange, slightly biconvex, round film-coated tablets with functional scoring, engraved "IMA" over score "100" on one side, "APO" on the other side Bottles of 30 tablets……………………….…………NDC 60505-2900-3 Bottles of 90 tablets………………………………….NDC 60505-2900-9 Bottles of 100 tablets………………………………….NDC 60505-2900-1 Bottles of 1,000 tablets……………………………….NDC 60505-2900-8 Blisters of 100 tablets (10 x 10)………………….….NDC 60505-2900-0 400 mg Tablets Brownish orange, capsule shaped, biconvex film-coated tablets with functional scoring, engraved "IMA" score "400" on one side, "APO" on the other side Bottles of 30 tablets……………………………….….NDC 60505-2901-3 Bottles of 90 tablets………………………………….NDC 60505-2901-9 Bottles of 100 tablets………………………………….NDC 60505-2901-1 Bottles of 500 tablets………………………………….NDC 60505-2901-5 Blisters of 100 tablets (10 x 10)…………….……….NDC 60505-2901-0 Storage and Handling Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted from 15°C to 30ºC (59°F to 86ºF) .

Protect from moisture.

Dispense in a tight container, USP.

Do not crush imatinib mesylate tablets.

Avoid direct contact of crushed tablets with the skin or mucous membranes.

If such contact occurs, wash thoroughly as outlined in the references.

Avoid exposure to crushed tablets.

Imatinib mesylate tablets can cause fetal harm when administered to a pregnant woman based on human and animal data.

There are no clinical studies regarding use of imatinib mesylate tablets in pregnant women.

There have been postmarket reports of spontaneous abortions and congenital anomalies from women who have been exposed to imatinib mesylate tablets during pregnancy.

Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity and increased incidence of congenital abnormalities following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800 mg/day based on BSA.

Advise women to avoid pregnancy when taking imatinib mesylate tablets.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is not known; however, in the U.S. general population, the estimated background risk of major birth defects of clinically recognized pregnancies is 2% to 4% and of miscarriage is 15% to 20%.

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of imatinib mesylate up to 100 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis.

In rats, imatinib mesylate was teratogenic at 100 mg/kg/day (approximately equal to the maximum human dose of 800 mg/day based on BSA), the number of fetuses with encephalocoele and exencephaly was higher than historical control values and these findings were associated with missing or underdeveloped cranial bones.

Lower mean fetal body weights were associated with retarded skeletal ossifications.

In rabbits, at doses 1.5 times higher than the maximum human dose of 800 mg/day based on BSA, no effects on the reproductive parameters with respect to implantation sites, number of live fetuses, sex ratio or fetal weight were observed.

The examinations of the fetuses did not reveal any drug related morphological changes.

In a pre.

• and postnatal development study in rats, pregnant rats received oral doses of imatinib mesylate during gestation (organogenesis) and lactation up to 45 mg/kg/day. Five animals developed a red vaginal discharge in the 45 mg/kg/day group on Days 14 or of gestation, the significance of which is unknown since all females produced viable litters and none had increased post-implantation loss.

Other maternal effects noted only at the dose of 45 mg/kg/day (approximately one-half the maximum human dose of 800 mg/day based on BSA) included an increased number of stillborn pups and pups dying between postpartum Days and 4.

In the

F1 offspring at this 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.

There were no other significant effects in developmental parameters or behavioral testing.

F 1 fertility was not affected but reproductive effects were noted at 45 mg/kg/day, including an increased number of resorptions and a decreased number of viable fetuses.

The no-observed-effect level (NOEL) for both maternal animals and the F1 generation was 15 mg/kg/day.

Imatinib and its active metabolite are excreted into human milk.

Because of the potential for serious adverse reactions in breastfed infants from imatinib mesylate, advise a lactating woman not to breastfeed during treatment and for 1 month after the last dose.

Based on data from three breastfeeding women taking imatinib mesylate tablets, the milk: plasma ratio is about 0.5 for imatinib and about 0.9 for the active metabolite.

Considering the combined concentration of imatinib and active metabolite, a breastfed infant could receive up to 10% of the maternal therapeutic dose based on body weight.

The safety and effectiveness of imatinib mesylate tablets have been demonstrated in pediatric patients with newly diagnosed Ph+ chronic phase CML and Ph+ ALL.

There are no data in children under 1 year of age.

In the

CML clinical studies, approximately 20% of patients were older than 65 years.

In the study of patients with newly diagnosed CML, 6% of patients were older than 65 years.

The frequency of edema was higher in patients older than 65 years as compared to younger patients; no other difference in the safety profile was observed.

The efficacy of imatinib mesylate was similar in older and younger patients.

In the unresectable or metastatic

GIST study, 16% of patients were older than 65 years.

No obvious differences in the safety or efficacy profile were noted in patients older than 65 years as compared to younger patients, but the small number of patients does not allow a formal analysis.

In the adjuvant

GIST study, 221 patients (31%) were older than 65 years.

No difference was observed in the safety profile in patients older than 65 years as compared to younger patients, with the exception of a higher frequency of edema.

The efficacy of imatinib mesylate was similar in patients older than 65 years and younger patients.