Dosing and uses of Gleevec (imatinib)
Adult dosage forms and strengths
tablet
- 100mg
- 400mg
Acute Lymphoblastic Leukemia
Indicated for adults with relapsed or refractory Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL)
600 mg PO qDay
Myelodysplastic/Myeloproliferative Diseases
Indicated in adults with myelodysplastic/ myeloproliferative diseases associated with platelet-derived growth factor receptor gene re-arrangements as determined with an FDA-approved test
400 mg PO qDay
Hypereosinophilic Syndrome/Eosinophilic Leukemia
Indicated for adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFR-alpha fusion kinase (mutational analysis or FISH demonstration of CHIC2 allele deletion) and for patients with HES and/or CEL who are FIP1L1-PDGFR-alpha fusion kinase negative or unknown
400 mg PO qDay
In patients with demonstrated F1P1L1-PDGFR-alpha fusion kinase: 100 mg PO qDay; may increase to 400 mg qDay in the absence of adverse drug reactions if assessments demonstrate an insufficient response to therapy
Chronic Myeloid Leukemia
Chronic phase
- Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase
- 400 mg PO qDay
- Chronic phase after failure of interferon-alpha therapy: May increase to 600 mg/day in the absence of severe adverse drug reaction and severe nonleukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6-12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response
Accelerated phase or blast crisis
- 600 mg PO qDay
- May increase to 400 mg PO q12hr in the absence of severe adverse drug reaction and severe nonleukemia related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time), failure to achieve a satisfactory hematologic response after at least 3 months of treatment, failure to achieve a cytogenetic response after 6-12 months of treatment, or loss of a previously achieved hematologic or cytogenetic response
Dermatofibrosarcoma Protuberans
Indicated for adults with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans
400 mg PO q12hr
Mastocytosis
Indicated for adults with aggressive systemic mastocytosis without the D816V c-Kit mutation as determined with an FDA-approved test or with c-Kit mutational status unknown
Without D816V c-Kit mutation: 100 mg PO qDay
c-Kit mutational status unknown: 400 mg PO qDay if not responding to other therapies
ASM associated with eosinophilia (a clonal hematological disease related to the fusion kinase FIP1L1-PDGFR-alpha): 100 mg PO qDay initially, may increase to 400 mg/day in absence of adverse effects if response to therapy is insufficient
Gastrointestinal Stromal Tumors
Unresectable and/or metastatic malignant GISt
- 400 mg PO qDay; may increase to 400 mg BID in patients showing clear signs or symptoms of disease progression at a lower dose and in the absence of severe adverse drug reactions
Adjuvant treatment following complete gross resection of GISt
- 400 mg PO qDay x3 years
Dosage modifications
Withhold treatment if fluid retention
Hematologic toxicity
- Generally, discontinue if ANC <1000/mm³ and/or Plts <50,000/mm³
- Resume when ANC >1500/mm³ and Plts >75,000/mm³
- See Mfr's PI for specifics
Hepatotoxicity
- Withhold if bilirubin >3x ULN or ALT/AST >5x ULN
- Resume after bilirubin <1.5x ULN and ALT/AST <2.5x ULN at a reduced dose (ie, 400 mg to 300 mg; 600 mg to 400 mg; 800 mg to 600 mg)
- Withhold if severe hepatotoxicity; once resolved, reduce dose by 25%
Pulmonary Arterial Hypertension (Orphan)
Orphan indication sponsor
- Novartis Drug Regulatory Affairs; East Hanover, NJ 07936-1080
Progressive Multifocal Leukencephalopathy (Orphan)
Orphan designation for treatment of PML
Sponsor
- Inhibikase Therapeutics, Inc; 3350 Riverwood Parkway, Suite 1927; Atlanta, GA 30339
Dosing Considerations
Monitor
- CBC qWeek x 4, then q2Weeks x 2, then periodically
- LFTs at baseline and qMonth
- Signs of fluid retention
Administration
Take with meal and a large glass of water
For patients unable to swallow, tablets may be dispersed in water or apple juice
Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity
Pediatric dosage forms and strengths
tablet
- 100mg
- 400mg
Chronic Myeloid Leukemia
Indicated for newly diagnosed adult and pediatric patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase
<1 year: Safety and efficacy not established
≥1 year: 340 mg/m²/day PO; not to exceed 600 mg/day
Acute Lymphoblastic Leukemia
Indicated for treatment of newly diagnosed children with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL)
<1 year: Safety and efficacy not established
≥1 year: 340 mg/m²/day PO; not to exceed 600 mg/day
Dosage modifications
Withhold treatment if fluid retention
Hematologic toxicity
- Generally, discontinue if ANC <1000/mm³ and/or Plts <50,000/mm³
- Resume when ANC >1500/mm³ and Plts >75,000/mm³
- See Mfr's PI for specifics
Hepatotoxicity
- Withhold if bilirubin >3x ULN or ALT/AST >5x ULN
- Resume after bilirubin <1.5x ULN and ALT/AST <2.5x ULN at a reduced dose (ie, from 340 mg/m²/day to 260 mg/m²/day)
- Withhold if severe hepatotoxicity; once resolved reduce dose by 25%
Dosing Considerations
Monitor
- CBC qWeek x 4, then q2Weeks x 2, then periodically
- LFTs at baseline and qMonth
- Signs of fluid retention
Administration
Take with meal and large glass of water
For patients unable to swallow, tablets may be dispersed in water or apple juice
Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity
Gleevec (imatinib) adverse (side) effects
>10%
Edema (53%)
Neutropenia (Grade 3: 7-27%; Grade 4: 3-48%)
Nausea (43%)
Muscle cramps (35%)
Musculoskeletal pain (34%)
Thrombocytopenia (Grade 3: 1-31%; Grade 4: 1-34%)
Rash (32%)
Fatigue (31%)
Diarrhea (30%)
Headache (29%)
Arthralgia (27%)
Abd pain (23%)
Myalgia (21%)
Nasopharyngitis (19%)
Hemorrhage (19%)
Vomiting (15%)
Dyspepsia (15%)
Cough (13%)
Dizziness (13%)
URT infection (13%)
Fever (12%)
Weight gain (12%)
Hepatotoxicity (6-12%)
Insomnia (11%)
1-10%
Flushing
Palpitation
Dry skin
Erythema
Metabolic hyperglycemia
Stomatitis/mucositis
Lymphopenia
<1%
Aplastic anemia
Atrial fibrillation
Avascular necrosis
Cardiac failure
Cardiogenic shock
Embolism
Eosinophilia
Postmarketing Reports
Nervous system disorders: Cerebral edema
Eye disorders: Vitreous hemorrhage
Cardiac disorders: Pericarditis, cardiac tamponade
Vascular disorders: Thrombosis/embolism, anaphylactic shock
Respiratory, thoracic and mediastinal disorders: Acute respiratory failure, interstitial lung disease
Gastrointestinal disorders: Ileus/intestinal obstruction, tumor hemorrhage/tumor necrosis, gastrointestinal perforation, diverticulitis; gastric antral vascular ectasia
Skin and subcutaneous tissue disorders: Ichenoid keratosis, lichen planus, toxic epidermal necrolysis, palmar-plantar erythrodysesthesia syndrome, drug rash with eosinophilia and systemic symptoms (DRESS)
Musculoskeletal and connective tissue disorders: Avascular necrosis/hip osteonecrosis, rhabdomyolysis/myopathy, growth retardation in children
Reproduction disorders: Hemorrhagic corpus luteum/hemorrhagic ovarian cyst
Warnings
Contraindications
Hypersensitivity to any component
Cautions
Hepatic impairment, elderly
Avoid concomitant strong CYP3A4 inducers
Inhibits CYP 2C9, 2D6, and 3A4
Risk of severe CHF or left ventricular dysfunction, especially in patients with comorbidities; monitor and treat patients with cardiac disease or risk factors for cardiac failure
In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cases of cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon initiation of imatinib therapy; reported to be reversible with the administration of systemic steroids, circulatory support measures, and temporarily withholding imatiniB
If anticoagulation required, use LMW or standard heparin instead of warfarin
Associated with anemia, neutropenia, and thrombocytopenia; CBC counts should be performed weekly for the first month, biweekly for the second month, and periodically thereafter
Hemorrhage may occur
Sometimes associated with GI irritation; should be taken with food and a large glass of water to minimize this problem.; there have been rare reports, including fatalities, of gastrointestinal perforation
Avoid pregnancy; risk of embryo-fetal toxicity
Often associated with edema and occasionally serious fluid retention; probability increases with dose and age >65 yr; investigate unexpected raid weight gain and provide appropriate treatment
Growth retardation may occur in children and adolescents
Bullous dermatologic reactions reported and include erythema multiforme and Stevens-Johnson syndrome
Cases of tumor lysis syndrome reported, including fatal cases
Assess liver function before initiation of treatment and monthly thereafter or as clinically indicated; monitor liver function when combined with chemotherapy known to be associated with liver dysfunction
Grade 3/4 hemorrhage reported in clinical studies in patients with newly diagnosed CML and with GIST; GI tumor sites may be the source of GI bleeds in GISt
Hypothyroidism reported in thyroidectomy patients undergoing levothyroxine replacement; closely monitor TSH levels in such patients
Motor vehicle accidents reported with therapy; caution patients about driving a car or operating machinery
Pregnancy and lactation
Pregnancy: Gleevec can cause fetal harm when administered to a pregnant woman based on human and animal data; there are no clinical studies regarding use of drug in pregnant women; there have been post-market reports of spontaneous abortions and congenital anomalies from women exposed to drug during pregnancy; advise women to avoid pregnancy during therapy; if drug is used during pregnancy, or if patient becomes pregnant while receiving therapy, apprise patient of potential hazard to fetus
Lactation: Imatinib and its active metabolite are excreted into human milk; advise a lactating woman not to breastfeed during treatment and for 1 month after last dose
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Gleevec (imatinib)
Mechanism of action
Protein-tyrosine kinase inhibitor, specific for abnormal BCR-ABL tyrosine kinase produced by Philadelphia chromosome in CML/ALL
Absorption
Bioavailability: 98%
Peak Plasma Time: 2-4 hr
Distribution
Protein Bound: 95%
Metabolism
Metabolized mostly by CYP3A4
Enzymes inhibited: CYP2D6, CYP3A4
Elimination
Half-Life: 18 hr (parent drug); 40 hr (metabolite)
Clearance: 8-14 L/hr
Excretion: Feces (68%)
Dialyzable: no
Pharmacogenomics
Tyrosine kinase inhibitors (TKIs) inhibit activity of BCR-ABL fusion protein, resulting in both hematologic response (ie, normal cell counts in the peripheral blood and normal bone marrow morphology), as well as cytogenetic response (ie, disappearance or reduction of the Philadelphia [Ph] chromosome)
NCCN clinical practice guidelines recommends TKIs in CML with confirmed BCR-ABL transcripts in bone marrow or evidence of translocation on cytogenetics
Genetic testing laboratories
- The following companies currently offer FISH and/or transcript quantification testing for BCR-ABL
- Asuragen (https://www.asuragen.com/)
- Dako (https://www.dakousa.com/)
- Invitrogen (https://www.invitrogen.com/)
- Ipsogen (https://www.ipsogen.com)
