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Imatinib (Systemic)


VA CLASSIFICATION
Primary: AN300

Commonly used brand name(s): Gleevec.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Leukemia, chronic myeloid (treatment)—Imatinib is indicated for the treatment of patients with chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.{01}

Note: Effectiveness is based on overall hematologic and cytogenetic response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.{01}{08}


Tumors, gastrointestinal stromal (treatment)1—Imatinib is indicated for the treatment of Kit (CD117) positive unresectable and/or metastatic gastrointestinal stromal tumors (GISTs). {03}{04}{05}{06}{07}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    589.7 {01}

Solubility
    Very soluble in water and soluble in aqueous buffers (pH £ 5.5), with variable solubility in non-aqueous solvents. Very slightly soluble to insoluble in neutral/alkaline aqueous buffers. {01}

Mechanism of action/Effect:

A protein-tyrosine kinase inhibitor, imatinib mesylate, inhibits the abnormally functioning Bcr-Abl tyrosine kinase which is produced by the Philadelphia chromosome abnormality found in chronic myeloid leukemia (CML). Imatinib inhibits cell proliferation and induces apoptosis (programmed cell death) in the Bcr-Abl cell lines and in the leukemic cells generated by CML. {01} Imatinib also inhibits proliferation and induces apoptosis in gastrointestinal stromal tumor (GIST) cells, which express an activating c-kit mutation. {07}


Other actions/effects:

In vitro studies demonstrate that imatinib is not entirely selective, as it also inhibits c-Kit and the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF) (including PDGF- and SCF-mediated cellular events). {01}

Absorption:

After oral administration, imatinib is well absorbed with a mean absolute bioavailability of 98%. {01}

Protein binding:

Very high (95%), mostly albumin and 1-acid glycoprotein. {01}

Biotransformation:

Via hepatic metabolism and cytochrome P450 enzymes (especially CYP3A4), imatinib is converted to its main circulating active metabolite, a N-demethylated piperazine derivative. This derivative, as shown in vitro, has similar potency to imatinib and comprises about 15% of the AUC (“area under the curve”) for imatinib. {01}

Half-life:

Elimination— Approximately 18 and 40 hours, for imatinib and its primary metabolite, respectively. {01}

Time to peak concentration:

2 to 4 hours. {01}

Elimination:
    Fecal—68% within 7 days (20% of dose unchanged). {01}
    Renal—13% within 7 days (5% of dose unchanged). {01}

Other actions/effects:

Note: The pharmacokinetics of imatinib were similar in CML and GIST patients. {07}





Precautions to Consider

Carcinogenicity

Studies have not been done. {01}

Tumorigenicity

Studies have not been done. {01}

Mutagenicity

Positive genotoxic effects were demonstrated in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. Two intermediates, present in the final product, are positive for mutagenesis in the Ames assay. {01}

Pregnancy/Reproduction
Fertility—
In both male and female rat fertility studies, negative effects were not seen when rats were given doses £ 20 mg per kg (mg/kg). After dosing male rats at 60 mg/kg (approximately equal to maximum clinical dose for humans or 800 mg/day, based on body surface area) for 70 days prior to mating, testicular and epididymal weights and percent motile sperm were decreased. After dosing female rats at 60 mg/kg, post-implantation fetal loss significantly increased and the number of live fetuses decreased. {01}

Pregnancy—
No adequate and well controlled studies have been done in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant. If imatinib is used during pregnancy or if the patient becomes pregnant while taking imatinib, the patient should be told of the potential hazard to the fetus. {01}

Imatinib was teratogenic in rats when given during organogenesis at doses ³ 100 mg/kg (approximately equal to the maximum clinical dose for humans or 800 mg/day, based on body surface area). These effects included: exencephaly or encephalocele, absent or reduced frontal bones, and absent parietal bones. At doses more than 100 mg/kg, total fetal loss occurred in all animals. {01}

FDA Pregnancy Category D. {01}

Breast-feeding

It not known whether imatinib or its metabolites are distributed into human breast milk. It is estimated that approximately 1.5% of a maternal dose of imatinib is distributed into breast milk. Although very little information is available regarding distribution of antineoplastic agents in human breast milk, breast-feeding is not recommended during chemotherapy because of the potential risks to the infant (adverse effects, mutagenicity, carcinogenicity). Imatinib is distributed into the milk of rats. {01}

Pediatrics

Appropriate studies on the relationship of age to the effect of imatinib have not been performed in the pediatric population. Safety and efficacy have not been established in pediatric patients under 18 years of age. {01}


Geriatrics


Appropriate CML clinical studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of imatinib in the elderly. A higher frequency of edema has occurred in patients > 65 years of age. In the GIST study, no obvious differences in the safety or efficacy were noted in patients >65 years; however, the small number of patients (29% >60 years and 10% >70 years) limits a formal analysis. {01} {07}


Dental

The bone marrow depressant effects of imatinib may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible, should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular toothbrushes, dental floss, and toothpicks.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Blood dyscrasia–causing medications (see Appendix II)    (neutropenic and/or thrombocytopenic effects of imatinib may be increased with concurrent or recent therapy if these medications cause the same effects; dosage adjustment of imatinib, if necessary, should be based on blood counts; cytopenias are dependent on the stage of disease and are more frequent in accelerated phase CML or blast crisis than in chronic phase CML {01})


» Bone marrow depressants, other (see Appendix II) or
Radiation therapy    (additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively)


» Enzyme Inducers, hepatic, cytochrome P450 (isoenzyme CYP3A4), including (see Appendix II):
Carbamazepine or
Dexamethasone or
Phenobarbital or
Phenytoin or
Rifampicin or
St. John's Wort    (CYP3A4 inducers may increase imatinib metabolism and therefore decrease imatinib plasma concentrations; no specific studies have been performed; caution is warranted {01})


» Enzyme Inhibitors, hepatic, cytochrome P450 (isoenzyme CYP3A4), including (see Appendix II):
Clarithromycin or
Erythromycin or
Grapefruit juice {02}
Itraconazole or
Ketoconazole    (CYP3A4 inhibitors may decrease imatinib metabolism and therefore increase imatinib plasma concentrations; caution is warranted; significant increase in imatinib plasma concentration with concurrent use of ketoconazole {01})


Enzyme Substrates, hepatic, cytochrome P450 (isoenzyme CYP2D6), including:
Beta-blockers
Cyclophosphamide
Morphine
Oxycodone
Serotonin-H3 antagonists    (imatinib may increase the plasma concentration of other CYP2D6 metabolized medications; imatinib inhibits the isoenzyme CYP2D6 in vitro; no specific studies have been performed; caution is recommended {01} {02} {07})


» Cyclosporine or
Dihydropyridine calcium channel blockers or
» Pimozide or
Simvastatin or
HMG-CoA reductase inhibitors, other, certain or
Triazolo-benzodiazepines    (imatinib may increase the plasma concentration of other CYP3A4 metabolized medications; use caution as some medications have a narrow therapeutic window {01})


Vaccines, killed virus    (because normal defense mechanisms may be suppressed by imatinib therapy, the patient's antibody response to the vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medications used, the underlying disease, and other factors; estimates vary from 3 months to 1 year)


» Vaccines, live virus    (because normal defense mechanisms may be suppressed by imatinib therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the imatinib therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medications used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. Immunization with oral poliovirus vaccine should also be postponed in persons in close contact with the patient, especially family members)


» Warfarin    (patients who require anticoagulation should receive low-molecular weight or standard heparin due to competitive metabolism with the CYP2C9 and CYP3A4 isoenzymes by imatinib {01}{07})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory values
Alanine aminotransferase (ALT [SGPT]), serum and
Alkaline phosphatase, serum and
Aspartate aminotransferase (AST [SGOT]), serum and
Bilirubin, serum
Creatinine, serum    (values may be increased during therapy{01}{07})


Albumin    (value may be decreased during therapy {07})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to imatinib{01}
Risk-benefit should be considered when the following medical problems exist
» Anemia or
» Leukopenia or
» Neutropenia or
» Thrombocytopenia    (if severe, should be corrected before initiation of imatinib therapy; patients should be closely monitored{01})


» Bone marrow depression
» Caution should be used in patients who have had previous cytotoxic drug therapy and radiation therapy.
» Chickenpox, existing or recent (including recent exposure) or
» Herpes zoster    (risk of severe generalized disease)


» Hepatic impairment    (exposure to imatinib may be increased; patients should be closely monitored{01})


» Infection

Patient monitoring
The following are especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase, serum and
Aspartate aminotransferase (AST [SGOT]) and
Bilirubin, serum    (determinations recommended prior to initiation of therapy and then monthly or as clinically indicated; {01} treatment with imatinib may cause Grade 3 severity liver function tests, especially seen in myeloid blast and accelerated phase clinical trials {01})


Blood urea nitrogen (BUN) concentrations and
Creatinine, serum    (recommended at periodic intervals during therapy; no long-term safety studies have been done on humans; some animal testing has demonstrated potential toxicity with long-term use {01})


» Hematocrit or hemoglobin and
» Leukocyte count, total and, if appropriate, differential and
» Platelet count    (complete blood counts recommended after start of therapy: weekly for 1 month, biweekly for the second month, then periodically as clinically indicated {01})


Weight    (monitor regularly for unexpected rapid weight gain; severe fluid retention and superficial edema reported in 1–8% of patients{01}{07})




Side/Adverse Effects

Note: Many side effects of antineoplastic therapy are unavoidable and represent the medication's pharmacologic action. Some of these (for example, leukopenia, neutropenia, and thrombocytopenia) are actually used as parameters to aid in individual dosage titration.
The majority of patients treated with imatinib experienced adverse effects during treatment, most of which were mild to moderate in severity. {01}
A mix of adverse effects represent local or general fluid retention including pleural effusion, ascites, pulmonary edema, and rapid weight gain (with or without superficial edema). Severe cases occurred in 2 to 8% of patients taking imatinib for CML. Severe superficial edema was reported in 2 to 5% of the patients with CML. In patients taking imatinib for GIST, severe superficial edema and severe fluid retention (pleural effusion, pulmonary edema and ascites) were reported in 1 to 6%.. These adverse effects, which seem dose related, were more common in the blast crisis and accelerated phase studies (dose of 600 mg/day) and were more common in the elderly. Treatment of these effects were usually managed by treatment cessation and with diuretics and other supportive care measures. Some of these adverse effects can be serious or life threatening. {01} {07}
Adverse effects are reported without establishment of a cause and effect relationship to the treatment. {01} {02} {07}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent (>25%)
    
Anemia (pale skin; troubled breathing, exertional; unusual bleeding or bruising; unusual tiredness or weakness)
    
edema (decreased urination; rapid weight gain; bloating or swelling of face, hands, lower legs, and/or feet)—more common in the elderly; may involve local or general fluid retention, watch for pleural effusion or pulmonary edema
    
hemorrhage (bleeding problems)
    
neutropenia (black, tarry stools; chest pain; chills; cough; fever ; painful or difficult urination; shortness of breath; sore throat; sores, ulcers, or white spots on lips or in mouth; swollen glands; unusual bleeding or bruising; unusual tiredness or weakness)—episode duration usually lasts two to three weeks
    
thrombocytopenia (black, tarry stools; chest pain; chills; cough; fever; painful or difficult urination; shortness of breath; sore throat; sores, ulcers, or white spots on lips or in mouth; swollen glands; unusual bleeding or bruising; unusual tiredness or weakness)—episode duration usually lasts three to four weeks
{01}{07}
Incidence less frequent (10–25%)
    
Dyspnea (shortness of breath; difficult or labored breathing )
    
hypokalemia (convulsions; decreased urine; dry mouth; irregular heartbeat; increased thirst; loss of appetite ; mood changes; muscle pain or cramps; nausea or vomiting; numbness or tingling in hands, feet, or lips; shortness of breath; unusual tiredness or weakness)
    
influenza (chills; cough, nonproductive; fever, abrupt onset; general feeling of discomfort or illness ; headache; muscle aches and pains; runny nose; shivering; sore throat ; sweating; unusual tiredness or weakness )
    
petechiae (small red or purple spots on skin)
    
pneumonia ( chest pain; cough; fever or chills; sneezing; shortness of breath; sore throat; troubled breathing; tightness in chest; wheezing)
    
upper respiratory tract infection (ear congestion; nasal congestion ; chills; cough; fever ; sneezing; sore throat; body aches or pain; headache; loss of voice ; runny nose; unusual tiredness or weakness ; difficulty in breathing)

{01}{07}Incidence rare (<10%)
    
Cerebral hemorrhage (blurred vision; headache sudden and severe; inability to speak; seizures ; slurred speech; temporary blindness; weakness in arm and/or leg on one side of the body, sudden and severe )
    
gastrointestinal hemorrhage ( black, tarry stools; bloody stools; vomiting of blood or material that looks like coffee grounds)
    
tumor hemorrhage —GIST only

{01}{07}

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (>25%)
    
Abdominal pain (stomach pain){07}
    
arthralgia (joint pain)
    
diarrhea (increased bowel movements; loose stools)
    
fatigue (unusual tiredness or weakness)
    
headache
    
muscle cramps
    
musculoskeletal pain (muscle or bone pain)
    
myalgia (muscle pain)— reported less frequent for CML
    
nausea and vomiting
    
skin rash
    
pyrexia (fever)— reported less frequent for GIST
    
weight gain
{01}{07}
Incidence Less Frequent (10–25%)
    
Anorexia (loss of appetite; weight loss)
    
asthenia (lack or loss of strength)
    
back pain
    
constipation (difficulty having a bowel movement (stool))
    
cough
    
dizziness
    
dyspepsia (acid indigestion ; upset stomach)
    
ecchymoses (bruising; large, flat, blue or purplish patches in the skin)
    
epistaxis ( bloody nose)
    
flatulence ( bloated full feeling; excess air or gas in stomach or intestines ; passing gas)
    
insomnia (sleeplessness; trouble sleeping; unable to sleep)
    
lacrimation, increased (watering of eyes)
    
nasopharyngitis (stuffy nose; sore throat)
    
night sweats
    
pruritus (itching skin)
    
rigors (feeling unusually cold; shivering )
    
sore throat
    
taste disturbance (change in taste; bad unusual or unpleasant (after)taste)
    
weakness
{01}{07}




Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
Experience with doses greater than 800 mg is limited.{01}

Treatment of overdose
There is no known specific antidote to imatinib. Treatment is generally symptomatic and supportive.{01}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Imatinib (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to imatinib

Pregnancy—Not recommended for use during pregnancy





Breast-feeding—Not recommended because of risk of serious side effects





Use in children—Safety and efficacy not established in children under 18 years of age






Use in the elderly—Higher frequency of edema
Other medications and foods, especially bone marrow depressants, carbamazepine, clarithromycin, cyclosporine, dexamethasone, erythromycin, grapefruit juice, itraconazole, ketoconazole, phenobarbital, phenytoin, pimozide, rifampicin, St. John's Wort, vaccines (live virus), or warfarin
Other medical problems, especially anemia, bone marrow depression, chicken pox, herpes zoster, infection, leukopenia, neutropenia, hepatic function impairment, or thrombocytopenia

Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed

» Taking medication with food and water

Importance of not taking imatinib with grapefruit juice, grapefruit, or grapefruit-containing products.

» Proper dosing
Not taking at all; not doubling doses

Proper storage

Precautions while using this medication
» Importance of close monitoring by the physician

» Avoiding immunizations unless approved by physician; other persons in patient's household should avoid immunizations with oral poliovirus vaccine; avoiding other persons who have taken oral poliovirus vaccine or wearing a protective mask that covers nose and mouth

Caution if bone marrow depression occurs
» Avoiding exposure to persons with infections, especially during period of low blood counts; checking with physician immediately if fever or chills, cough or hoarseness, lower back or side pain, or painful or difficult urination occurs

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine; or pinpoint red spots on skin occur

Caution in use of regular toothbrush, dental floss, or toothpick; physician, dentist, or nurse may suggest alternatives; checking with physician before having dental work done

Not touching eyes or inside of nose unless hands washed immediately before

Using caution to avoid accidental cuts with use of sharp objects such as safety razor or fingernail or toenail cutters

Avoiding contact sports or other situations where bruising or injury could occur


Side/adverse effects
Signs of potential side effects, especially anemia, edema, hemorrhage, neutropenia, thrombocytopenia, dyspnea, hypokalemia, petechiae, pneumonia, upper respiratory tract infection, cerebral hemorrhage, gastrointestinal hemorrhage, or tumor hemorrhage


General Dosing Information
Treatment with imatinib should be initiated by a physician experienced with CML or GIST treatment and should continue as long as the patient benefits. {01} {07}

Treatment with imatinib is often associated with cytopenias (neutropenia or thrombocytopenia). Complete blood counts should be done weekly for the first month, biweekly for the second month, and periodically as clinically indicated (e.g., every two to three months). Cytopenias are dependent on the disease stage and are more frequent in patients with accelerated phase CML of blast crisis than in patients with chronic phase CML. {01} In the GIST trial, cytopenias were more frequent at a dose of 600 mg and in patients with Grade 3 disease. {07}

Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of imatinib. These may include: extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool and secretions for occult blood; care in use of toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and any aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.

Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests.

Diet/Nutrition
Imatinib sometimes causes gastrointestinal irritation and should be taken with food and a large glass of water to minimize this problem. {01}

Imatinib should not be taken with grapefruit juice due to the possible inhibition of the metabolism of imatinib by substances in grapefruit. {02}

For treatment of adverse effects
Many toxicity-related problems, such as kidney and liver toxicity, or immunosuppression can usually be managed by dose reduction and/or treatment interruption. Toxicities may develop from long-term use (more than six months) of imatinib and no long-term safety data exists. {01}


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.


IMATINIB MESYLATE CAPSULES

Note: Dose and strength of imatinib mesylate are expressed in terms of the base.


Usual Adult Dose
Leukemia, chronic myeloid, accelerated phase or blast crisis
Oral, 600 mg (base) once daily with a meal and a large glass of water. Treatment should continue as long as the patient continues to benefit. {01}

Note: Dose increase to 800 mg daily (given as 400 mg twice daily) 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 three months of treatment; loss of a previously achieved hematologic response. {01}


Note: Treatment changes for severe hematologic reactions (after at least one month of treatment): if absolute neutrophil count (ANC) drops below 0.5 x 109 cells/L and/or platelets drop below 10 x 109 cells/L, see procedure list (below): {01}
   #149; Check if cytopenia is related to leukemia by marrow aspirate or biopsy procedure.
   #149; If cytopenia is unrelated to leukemia, reduce imatinib dose to 400 mg/day.
   #149; If cytopenia persists for 2 weeks, further reduce imatinib dose to 300 mg/day.
   #149; If cytopenia persists for 4 weeks and is not related to leukemia, stop imatinib dosing until ANC increases to at least 1 x 10 9 cells/L and platelets increase to at least 20 x 10 9 cells/L. Then, resume treatment at 300 mg/day. {01}



Note: If a severe non-hematologic adverse reaction occurs (severe hepatotoxicity or severe fluid retention), imatinib treatment should be stopped until the event subsides. Treatment can be restarted as appropriate depending on the initial severity of the event. {01}
If bilirubin levels exceed more than 3 times the institutional upper limit of normal (IULN) or if liver transaminases exceed more than 5 times the IULN, stop imatinib treatment until bilirubin levels have dropped below 1.5 times the IULN or transaminase levels have dropped below 2.5 times the IULN. Then, imatinib treatment may continue at a reduced daily dose (i.e., from 600 to 400 mg). {01}


Leukemia, chronic myeloid, chronic phase
Oral, 400 mg (base) once daily with a meal and a large glass of water. {01}

Note: Dose increase to 600 mg daily 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 three months of treatment; loss of a previously achieved hematologic response. {01}


Note: Treatment changes for severe hematologic reactions: if absolute neutrophil count (ANC) drops below 1 x 109 cells/L and/or platelets drop below 50 x 109 cells/L, see procedure list (below): {01}
   #149; Stop imatinib dosing until ANC increases to at least 1.5 x 109 cells/L and platelets increase to at least 75 x 109 cells/L.
   #149; Resume imatinib treatment at dose of 400 mg/day.
   #149; If cytopenia recurs with the ANC dropping below 1 x 10 9 cells/L and platelets dropping below 50 x 10 9 cells/L, then stop imatinib dosing until ANC increases to at least 1.5 x 109 cells/L and platelets increase to at least 75 x 109 cells/L. Then, resume treatment at 300 mg/day. {01}




Note: If a severe non-hematologic adverse reaction occurs (severe hepatotoxicity or severe fluid retention), imatinib treatment should be stopped until the event subsides. Treatment can be restarted as appropriate depending on the initial severity of the event. {01}
If bilirubin levels exceed more than 3 times the institutional upper limit of normal (IULN) or if liver transaminases exceed more than 5 times the IULN, stop imatinib treatment until bilirubin levels have dropped below 1.5 times the IULN or transaminase levels have dropped below 2.5 times the IULN. Then, imatinib treatment may continue at a reduced daily dose (i.e., from 400 to 300 mg ). {01}

Tumors, gastrointestinal stromal1
Oral, 400 mg per day, increasing to 600 mg per day as needed. {06} {07}


Usual Pediatric Dose
Safety and efficacy have not been established. {01}

Usual Geriatric Dose
See Usual adult dose.

Strength(s) usually available
U.S.—


100 mg (base) (Rx) [Gleevec ( colloidal silicon dioxide) (crospovidone) (gelatin) (iron oxides) (magnesium stearate) (microcrystalline cellulose) (titanium dioxide)]{01}

Canada—


100 mg (base) (Rx) [Gleevec ( colloidal anhydrous silica ) (colloidal silicon dioxide) (crospovidone) ( gelatin) (iron oxides) ( magnesium stearate) (microcrystalline cellulose ) (titanium dioxide)]{02}

Packaging and storage:
Store at 25 °C (77 °F), excursions permitted between 15 and 30 °C (59 and 86 °F). Store in a tight container. {01}

Auxiliary labeling:
   • Keep container tightly closed.



Developed: 06/08/2001
Revised: 12/05/2002



References
  1. Product Information: Gleevec™, imatinib mesylate. Novartis Pharmaceuticals Corporation, East Hanover, NJ (PI issued 5/2001) reviewed 5/2001.
  1. Product Information: Gleevec™, imatinib mesylate. Novartis Pharmaceuticals Canada Inc., Dorval, Quebec (PI issued 09/2001) reviewed 10/2001.
  1. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. New Engl J Med 2001; 344(14): 1052-6.
  1. Blanke CD, von Mehren M, Joensuu H, et al. Evaluation of the safety of an oral molecularly-targeted therapy, STI571, in patients (pts) with unresectable or metastatic gastrointestinal stromal tumors (GISTs) expressing c-kit (CD117). Proc Am Soc Clin Oncol 2001; 20: 1a [Abst 1].
  1. van Oosterom AT, Judson I, Verweij J, et al. STI 571, an active drug in metastatic Gastrointestinal Stromal Tumors (GIST), an EORTC phase I study. Proc Am Soc Clin Oncol 2001; 20: 1a [Abst 2].
  1. Reviewers' consensus on the use of imatinib for the treatment of gastrointestinal stromal tumors (GISTs), 8/27/01.
  1. Product Information: Gleevec™, imatinib mesylate. Novartis Pharmaceuticals Corporation, East Hanover, NJ (PI issued 1/2002) reviewed 5/2002.
  1. Expert Committee comment on monograph revision of 10/02.
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