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iMAtinib
Imatinib is an inhibitor of multiple tyrosine kinases including c-Kit, Abl, SCF and PDGFR. Imatinib may thus be active in diseases where these are mutated, constitutively activated, have fusion proteins or dysregulated pathways, such as Philadelphia chromosome positive leukemia, GIST, myelodysplastic syndromes and some sarcomas. The Philadelphia chromosome, characteristic of chronic myelogenous leukemia (CML), is created by a reciprocal translocation between chromosomes 9 and 22, and results in production of a constitutively activated kinase (Bcr-Abl tyrosine kinase).
| Bioavailability |
98% |
| Effects with food |
High fat meals reduce absorption (11%) and exposure (7.4 %), but not clinically significant. |
Imatinib has a linear and dose-dependent pharmacokinetic profile. Daily dosing leads to a 1.5-2.5 fold accumulation at steady state. Body weight and gender do not appear to affect imatinib pharmacokinetics
| Cross blood brain barrier? | No information found (unlikely) |
| PPB | 95% (albumin, α1-acid glycoprotein) |
Imatinib is mainly metabolized by the CYP3A4 enzyme; other cytochrome P450 iso-enzymes (CYP1A2, CYP2D6, CYP2C9, CYP2C19) play minor roles in the metabolism of imatinib.
| Active metabolites |
Yes |
| Inactive metabolites |
Yes |
Imatinib is eliminated predominantly by fecal excretion (68%) and in urine (13%) within 7 days.
| Half-life | 18 hours |
- Chronic myeloid leukemia (CML)
- Acute lymphoblastic leukemia (ALL)
- Aggressive systemic mastocytosis (ASM) and Systemic mastocytosis with an associated clonal hematological non-mast-cell disorder (SM-AHNMD)
- Dermatofibrosarcoma protuberans (DFSP)
- Myelodysplastic / myeloproliferative diseases (MDS/MPD)
- Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL)
- Gastrointestinal stromal tumours (GIST)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
The following table contains adverse effects and incidences reported in newly diagnosed CML patients. Also includes rare side effects reported in post-marketing and other clinical studies.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (rare) | E | |||
| Arterial thromboembolism (rare) | E | ||||
| Cardiotoxicity (rare) | E | ||||
| Pericarditis , tamponade (rare) | E | ||||
| Pulmonary hypertension (rare) | E | ||||
| Venous thromboembolism (rare) | E | ||||
| Dermatological | Alopecia (5%) | E | |||
| Hand-foot syndrome (1%) | E | ||||
| Photosensitivity (<10%) | E | ||||
| Rash (40%) (may be severe) | E | ||||
| Gastrointestinal | Abdominal pain (37%) | E | |||
| Anorexia (7%) | E D | ||||
| Constipation (11%) | E | ||||
| Diarrhea (45%) | E | ||||
| Dyspepsia (19%) | E | ||||
| GI obstruction (rare) | E | ||||
| GI perforation (rare) | E | ||||
| Nausea, vomiting (50%) | I | ||||
| General | Fatigue (39%) | I E | |||
| Fluid retention (including effusions) (62%) | E D | ||||
| Flu-like symptoms (18%) | I E | ||||
| Hematological | Hemorrhage (including CNS, GI hemorrhage) | E | |||
| Myelosuppression ± infection, bleeding (grade 3 and 4: 17%, may be severe) | E | ||||
| Hepatobiliary | ↑ LFTs (12%) (may be severe) | E D | |||
| Pancreatitis (<1%) | E | ||||
| Hypersensitivity | DRESS syndrome (rare) | E | |||
| Hypersensitivity (rare) | I | ||||
| Infection | Infection (31%) (including opportunistic and atypical infections; HBV reactivation) | E | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (24%) | E | |||
| Hypothyroidism (rare) | D | ||||
| Tumour lysis syndrome (rare) | I E | ||||
| Musculoskeletal | Avascular necrosis (rare) | E | |||
| Musculoskeletal pain (50%) (includes withdrawal syndrome) | E | ||||
| Osteonecrosis (rare) | D L | ||||
| Rhabdomyolysis (or myopathy; rare) | E | ||||
| Nervous System | Anxiety (10%) | E | |||
| Confusion (or cognitive changes, < 1%) | E | ||||
| Depression (15%) (may be severe) | E | ||||
| Dizziness (19%) | E | ||||
| Headache (37%) (or migraine) | E | ||||
| Insomnia (15%) | E | ||||
| Paresthesia , optic neuritis (<10%) | E | ||||
| Ophthalmic | Conjunctivitis (<10%) | E | |||
| Renal | Renal failure (<1%) | E | |||
| Respiratory | Cough, dyspnea (20%) | E | |||
| Pneumonitis (rare) | D | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for imatinib include fluid retention (including effusions), musculoskeletal pain, nausea, vomiting, diarrhea, rash, fatigue, abdominal pain, headache, infection, bleeding and abnormal electrolyte(s).
Superficial edema was a common finding in all studies described primarily as periorbital edema or lower limb edema. Edema is rarely severe and may be managed with diuretics, other supportive measures, or by reducing the dose of imatinib. Severe fluid retention includes pleural effusion, pericardial effusion, pulmonary edema, ascites, or superficial edema and rapid weight gain. Interruption of imatinib treatment, diuretics and other supportive care measures usually managed these events. Edema and fluid retention are dose-related and are more common with higher doses.
Myelosuppression occurred frequently and incidence was more common at higher dosages, in blast crisis and accelerated phase than in the chronic phase of CML. Reducing the dosage or interrupting treatment will usually manage the cytopenic events, while hemoglobin usually returns to baseline values with continued therapy.
Reactivation of hepatitis B virus (HBV) has been reported in patients who are chronic carriers of HBV and received BCR-ABL TKI’s. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome. Patients should be tested for HBV infection prior to initiating treatment. Carriers of HBV must be monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy.
Subdural hematoma (up to 2%) has been reported with imatinib use with other risk factors, such as age > 50 years, thrombocytopenia (disease or medication-related), concurrent medications that increase bleeding risk, prior lumbar puncture or head trauma. Patients who experience head trauma or have unusual neurologic symptoms should be evaluated for subdural hematoma.
Gastric antral vascular ectasia (GAVE), a rare cause of gastrointestinal hemorrhage was reported in post-marketing after about one year of treatment (variable onset). Monitor patients for symptoms of GI hemorrhage throughout therapy and consider imatinib discontinuation, as appropriate.
Hepatotoxicity was reported with severe elevation of transaminases or bilirubin and may be fatal. Gastrointestinal or intratumour bleeds have been reported in patients with GIST, and concomitant use of warfarin or antiplatelet agents should be avoided.
Falls in LVEF and cardiac failure have been reported especially in patients with pre-existing risk factors such as hypertension, coronary artery disease and diabetes. Cardiogenic shock has been reported in patients with hypereosinophilia and cardiac involvement and may be reversible with steroids and supportive care.
GI obstruction and perforation has been reported in all tumour types.
Severe skin reactions have been observed including Stevens-Johnson syndrome, toxic epidermal necrolysis, leucocytoclastic vasculitis, Sweet's syndrome, erythema multiforme and DRESS (Drug reaction with eosinophilia and systemic symptoms) which may be life-threatening.
Patients at risk of tumour lysis syndrome should have appropriate prophylaxis and be monitored closely.
Long term treatment with imatinib may result in declines in renal function. In treatment-naïve patients with newly-diagnosed CML initiated on imatinib among three Phase III trials, a progressive decline in eGFR from a median baseline value of 100 ml/min/1.73m2 to 85.5 ml/min/1.73m2 at 5 years was observed. A study evaluating the incidence of acute kidney injury and chronic kidney disease (CKD) in chronic-phase CML patients treated with tyrosine kinase inhibitors found that imatinib treatment was associated with a CKD incidence of 22% (Yilmaz 2015).
Musculoskeletal pain may persist for months in 18-46% of CML patients following discontinuation of long-term treatment (imatinib withdrawal symptoms).
Osteonecrosis has been reported, including severe cases requiring treatment discontinuation, and /or surgical intervention. The most affected site was the femur head; other affected sites included the tibia, femur shaft, jaw, finger, and calcaneus.
Refer to protocol by which patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Patients with hypereosinophilia (e.g. MDS, HES) should be started on 1-2mg/kg of prednisone at least 2 days before imatinib is started and continued for 1-2 weeks.
Dose levels are 200mg, 300mg, 400mg, 600mg, and 800mg.
|
Indication |
Daily Starting Dose |
Escalate? |
|
|
|
|||
|
CML |
New diagnosis |
400mg |
Yes1 → 600 or 800mg |
|
Chronic |
400mg |
Yes1→ 600 or 800mg |
|
|
Blast crisis/accelerated |
600mg |
Yes1 → 800mg |
|
|
ALL Ph+ (monotherapy)
|
600mg |
No |
|
| MDS/MPD | 400mg | No | |
|
Systemic mastocytosis – with eosinophilia |
100mg |
Yes2 → 400mg |
|
|
Systemic mastocytosis – no eosinophilia (mutation status unknown, cKIT negative or not responding to other treatment) |
400mg |
No |
|
|
HES/CEL |
100mg |
Yes2 → 400mg |
|
|
DFSP |
800mg |
No |
|
|
GIST (metastatic/unresectable) |
400mg or 600mg |
Yes2 → 600mg or 800mg |
|
|
GIST (adjuvant) (one year duration) |
400mg |
No |
|
|
|||
| Toxicity | Action |
| Fluid retention (grade 3,4 ) | Hold until ≤ grade 1; resume with 1 dose level ↓. |
| Rash (grade 3, 4) | Hold until ≤ grade 1; resume with 1 dose level ↓ or discontinue. |
| Bilirubin 3 x ULN OR AST or ALT > 5 x ULN |
Hold*; resume with 1 dose level ↓. |
| Hypotension / Hypersensitivity reaction | Hold, treat supportively, consider steroids. |
| Bleeding | Hold; consider discontinuing if severe. |
| Pneumonitis | Hold, investigate, consider discontinuing if confirmed. |
| DRESS | Consider discontinuing. |
Dosage with Myelosuppression:
Monotherapy:
|
|
ANC (x 109/L) |
Platelets (x 109/L) |
Action |
|
Accelerated, blast crisis CML |
< 0.5 |
< 10 |
|
|
All others: |
|||
|
Starting dose 100mg |
< 1 |
< 50 |
|
|
Starting dose 400-600mg |
< 1 |
< 50 |
|
|
Starting dose 800mg |
< 1 |
< 50 |
|
Imatinib is excreted via the liver and increased exposure is likely in the presence of hepatic impairment.
Starting Dose (for usual starting dose range of 400-800 mg daily):
|
Hepatic Impairment |
Recommended Imatinib Starting Dose |
|
Mild |
400 mg daily |
|
Moderate |
400 mg daily |
|
Severe |
200 mg daily; |
Toxicity During Treatment: Refer to Dosage with Toxicity section.
Imatinib is not excreted via the kidney to a significant extent; however, increased exposure and adverse effects are correlated with renal impairment. Exercise caution in patients with mild to moderate renal impairment.
Starting Dose (For usual starting dose range 400-800 mg daily):
|
Creatinine Clearance (mL/min) |
Recommended Imatinib Starting Dose |
|
40-59 |
400 mg daily.* Use with caution. |
|
20-29 |
400 mg daily.*† Use with caution. |
|
<20 or on hemodialysis |
Not recommended for use |
* May adjust dose based on toxicity, or for lack of efficacy if lower dose was tolerated.
† Doses ≥ 800 mg daily have not been studied.
Efficacy was similar in patients ≥ 65 years of age compared to younger patients in CML and adjuvant GIST.
In adjuvant GIST, no difference in safety was observed in patients aged ≥ 65 years compared to younger patients.
There is no experience with imatinib in CML in pediatric patients under 2 years of age. Very limited to no experience exists for imatinib in children in other indications. Children have a higher incidence of electrolyte and glucose abnormalities than adults. Start at 340mg/m2 (do not exceed 600mg). Reduce dose to 260mg/m2 as needed – consult product monograph for details. Monitor growth closely in children and adolescents under imatinib treatment as there have been case reports of growth retardation.
- Tablets should be administered whole with meal(s) and a large glass of water to reduce gastric irritation.
- Doses < 800mg should be given once daily; total daily doses of 800mg should be given as 400mg twice daily to reduce exposure to iron.
- If unable to swallow the tablet:
- The 400 mg tablet may be broken into two pieces; administer each piece with water, one after the other.
- Alternatively, tablet may be dispersed in water or apple juice (use 50 mL for 100 mg tablet, and 200 mL for a 400 mg tablet) immediately before drinking this mixture. Then, rinse the container with water or apple juice and drink this, to ensure no trace of the tablet is left.
- Avoid grapefruit, starfruit, Seville oranges, their juices or products during treatment.
- If a dose is missed, the patient should skip this dose and take the next dose at the usual time.
- If vomiting occurs after taking a dose, do not take an extra dose. Take the next dose at the usual time.
- Store at room temperature.
- Patients with hypersensitivity to imatinib or to any other components of this product
- Severe fluid retention may occur, especially with higher doses. Patients should be weighed and monitored regularly. Patients with pre-existing cardiac disease, risk factors for cardiac failure or the elderly should be monitored carefully and be treated appropriately.
- Severe bleeding, including GI, CNS and intra-tumoural, have been reported during clinical trials and post-marketing. Use caution with the concomitant use of imatinib and other drugs that may increase bleeding (e.g. anticoagulants, antiplatelets or prostacyclins). Consider the use of LMWH rather than warfarin if anticoagulation is required.
Other Drug Properties:
-
Carcinogenicity:
Neoplastic changes were observed in animal studies. Relevance of these findings for humans is unknown. In clinical trials, the numbers of cancers reported were similar to those expected in the general population.
-
Embryotoxicity:
Documented in animals
-
Fetotoxicity:
Documented in animals
-
Teratogenicity:
Documented in humans
-
Abortifacient effects:
Documented in humans
-
Pregnancy:
Imatinib is not recommended for use in pregnancy.
- Adequate contraception should be used by patients who can become pregnant and their partners during treatment, and for at least 15 days after the last dose.
- Adequate contraception should be used by patients who produce sperm and their partners during treatment, and for at least 6 months (general recommendation) after the last dose.
-
Excretion into breast milk:
Yes
-
Breastfeeding:
Breastfeeding is not recommended during treatment and for at least 15 days after the last dose.
-
Fertility effects:
Yes
Fertility may be affected in patients who produce sperm.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) | ↑ Imatinib exposure (40% with ketoconazole) | ↓ metabolism | Caution |
| CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc.) | ↓ Imatinib exposure (74% with rifampin) | ↑ metabolism | Caution; consider using drugs with less enzyme induction potential |
| CYP3A4 substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors) | ↑ plasma concentration of CYP3A4 substrate | Imatinib inhibits CYP 3A4 | Caution; especially drugs with narrow therapeutic index |
| CYP2D6 substrates (e.g. cyclophosphamide, beta blockers, morphine, oxycodone, metoprolol, serotonin-H3 antagonists) | ↑ plasma concentration of CYP2D6 substrate (23% for metoprolol) | Imatinib inhibits CYP2D6 | caution, especially drugs with narrow therapeutic index |
| CYP 2C9 substrates (e.g. warfarin) | ↑ substrates' concentrations, or ↑ anticoagulant effect for warfarin (theoretical) | Imatinib inhibits CYP2C9 at high doses | Caution, monitor INR closely with warfarin, especially during imatinib initiation or dose adjustments, or consider LMWH for coagulation |
| Antiplatelet agents or other anticoagulants | ↑ risk of bleeding | Additive | Avoid; if must co-administer, monitor INR and platelets closely |
| acetaminophen | Exacerbation of hepatotoxicity, increased acetaminophen exposure (fatal case reported) | inhibits o-glucuronidation | Caution; monitor LFTs |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline; weekly for first month, biweekly for second month, and as indicated thereafter (e.g. every 2 to 3 months) |
| Liver function tests | Baseline, monthly, or as clinically indicated |
Electrolytes, serum creatinine and creatinine clearance |
Baseline, monthly or as clinically indicated |
INR for patients taking warfarin, especially when starting treatment and with imatinib dose adjustments |
Baseline and as clinically indicated |
TSH levels in patients with previous thyroidectomy or patients on replacement therapy |
Baseline and as clinically indicated |
LVEF, in patients with known underlying heart disease or in elderly patients |
Baseline and as clinically indicated |
Close monitoring of growth in younger patients |
Baseline and as clinically indicated |
Platelet counts and prothrombin time when imatinib is used concurrently with anticoagulants, prostacyclins, or other medications that increase bleeding risk |
Baseline and periodic |
Clinical assessment of fluid retention (including weight monitoring), bleeding, infection, cardiac effects, thromboembolism, rhabdomyolysis, tumour lysis syndrome, osteonecrosis, gastrointestinal effects, pneumonitis, and rash |
At each visit |
Brain imaging for patients suspected of having subdural hemorrhage |
As clinically indicated |
Serum or urine pregnancy test in women of childbearing potential |
Within one week before starting treatment |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
EKG and troponin in patients with hypereosinophilia and cardiac involvement |
As clinically indicated |
ODB - General Benefit (ODB Formulary )
- iMAtinib - Refer to listed Health Canada indications for generic imatinib formulations. Patients must meet generic substitution policies for access to Gleevec®
BCR-ABL Tyrosine Kinase Inhibitors [GLEEVEC (imatinib mesylate), TASIGNA (nilotinib), BOSULIF (bosutinib), SPRYCEL (dasatinib), ICLUSIG (ponatinib hydrochloride)] - Risk of Hepatitis B Reactivation. Health Canada, May 4, 2016. [Accessed May 13, 2016]. Available from: http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2016/58222a-eng.php
Druker BJ, Sawyers CL. Kantarjian H, et al. Activity of a specific inhibitor or the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. NEJM 2001;344(14):1038-42.
Gibbons J, Egorin MJ, Ramanathan RK, et al. Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol; 2008; 26:570-576.
Lyseng-Williamson K, Jarvis B. Imatinib. Drugs 2001: 61(12): 1765-1776.
Product Monograph: Gleevec. Novartis Pharmaceuticals Canada. August 31, 2022.
Ramanathan RK, Egorin MJ, Takimoto CHM, et al. Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol; 2008; 26:563-569.
Savage DG, Antman KH. Imatinib Mesylate – a new oral targeted therapy. NEJM 2002; 346(9): 683-93,
Yilmaz M, Lahoti A, O’Brien S, et al. Estimated glomerular filtration rate changes in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. Cancer; 2015; 121(21): 3894-904.
December 2024 Modified Dosage with myelosuppression section
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